WO2020011789A1

WO2020011789A1 - Injectable suspensions

Info

Publication number: WO2020011789A1
Application number: PCT/EP2019/068420
Authority: WO
Inventors: Torbjörn BÄCKSTRÖM; Björn NORRLIND
Original assignee: Asarina Pharma Ab
Priority date: 2018-07-09
Filing date: 2019-07-09
Publication date: 2020-01-16

Abstract

The present invention relates to pharmaceutical and physically stable suspensions, comprising crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one; and mixture of acylglycerols, methods for manufacturing such suspensions and their use in treatment of disorders.

Description

INJECTABLE SUSPENSIONS

Field of the invention

The present invention relates to pharmaceutical and physically stable suspensions, comprising crystalline particles of 3-alpha-hydroxy-5-alpha- pregnan-20-one; and mixture of acylglycerols, methods for manufacturing such suspensions and their use in treatment of disorders.

Background of the invention

Brain excitability is defined as the level of arousal of an animal, for example a human, a continuum that ranges from coma/anesthesia to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. In the case of the GABA receptor complex, the effect on brain excitability is mediated by the neurotransmitter GABA. Approximately 40% of the neurons in the brain utilize GABA as a neurotransmitter.

3-alpha-hydroxy-5-alpha-pregnan-20-one is a steroid in the pregnane family which is a highly potent positive allosteric modulator of GABA_A-receptor activity and can be used for induction of sedation/anaesthesia, and have been suggested for treatment of amongst other, postpartum depression,

and essential tremor. 3-alpha-hydroxy-5-alpha-pregnan-20-one is poorly soluble in most therapeutically acceptable solvents, which makes it difficult to administer the compound to a patient. Further, 3-alpha-hydroxy-5-alpha- pregnan-20-one is rapidly metabolized and excreted and therefore it is highly desirable to provide an administration with a slow or extended release profile. Thus, there is a need to provide a formulation of 3-alpha-hydroxy-5-alpha- pregnan-20-one with satisfactory extended release and depot function.

Formulations comprising 3-alpha-hydroxy-5-alpha-pregnan-20-one are disclosed in WO2013112605 and formulations for intravenous administration are suggested for treatment of amongst other epilepsy, depression, anorexia, anxiety disorders, menstrual cycle related disorders, stress related disorders, migraine, Tourette’s syndrome, Fragile X syndrome and essential tremor and dementia.

An injectable slow release profile can be obtained by a suspension of a compound in a vehicle in which the compound has some degree of solubility. A drawback and obstacle with such suspensions with crystalline particles for injection is the risk that crystalline particles will grow for example via Ostwald ripening and, therefore said suspension may not be physically stable and become more or less impossible to inject through clinically suitable needles, since such particles will clog in the needle.

Thus, there is a need in the field to provide medical products comprising 3- alpha-hydroxy-5-alpha-pregnan-20-one, which products are safe, convenient to administer, stable, that provide a slow or extended release profile when injected, and/or allow for a high level of patient compliance.

Description of the invention

It is highly desirable, as an objective of the present invention, to provide a suspension comprising a sufficient content, such as at least 20 mg/mL, of 3- alpha-hydroxy-5-alpha-pregnan-20-one. Said suspension is preferably injectable through a 20G or 21 G needle or thinner, and is stable, wherein said steroid could exert its therapeutic effect in a sufficient manner. In particular, when a high administration dose of 3-alpha-hydroxy-5-alpha-pregnan-20-one is needed, needles of 20G or 21 G may be used. Herein are also provided suspensions, wherein the content of 3-alpha-hydroxy-5-alpha-pregnan-20- one of said suspension injectable through a 23G needle or thinner is about 20 to about 200 mg/mL. In particular there are provided suspensions, wherein the content of 3-alpha-hydroxy-5-alpha-pregnan-20-one of said suspension injectable through a 25G needle or thinner is about 20 to about 150 mg/mL. Further, it is highly desirable that said suspensions remain stable in order to provide a useful suspension also after long shelf time. Further, it is highly desirable, as an objective of the present invention, to provide a suspension that is sterile and thus suitable for human parenteral use.

It will be appreciated that it is outmost importance that a medicinal product, in particular a medicinal product for self-administration such as through a 23G or a 25G needle or thinner, is a product that is convenient and suitable for the patient to administer without any elaborate special technique. Further, it is necessary that the medicinal product is sterile and stable in order to provide a useful and safe product also after long shelf time.

Formulations of the structurally similar compound 3-beta-hydroxy-5-alpha- pregnan-20-one are known from WO2011/087441. Formulations of 3-alpha- hydroxy-5-alpha-pregnan-20-one and of other structurally related compounds may be prepared in the same manner as described in WO2011/087441.

Flowever, such formulations have the drawback that the methods by which suspensions are manufactured as described in WO2011/087441 are not ideal as a pharmaceutical injection product since the suspension must be stirred for several days. Stirring for several days is not an acceptable-manufacturing process according to industry standard and good manufacturing practice as an aseptic process to generate a sterile, parenteral product for human use. Pharmaceutical products for injections shall be sterilised through autoclaving, ionization radiation, or as in the case for the present invention when neither of these are possible, the product components shall be initially sterile and mixed under aseptic conditions (EMA’’Guideline on the sterilization of the medicinal product, active substance, excipient and primary container”

( EM A/C H M P/CVM P/Q W P/B W P/850374/2015). It is thus important that the 3-alpha-hydroxy-5-alpha-pregnan-20-one in the medicinal product has the appropriate physical and aseptic properties at the time of manufacture and remains physically stable for adequate time, such as 6 months, or more. Further, in some embodiments the suspension may preferably be injectable through a 23G or a 25G needle, or thinner.

Before the present invention is described in detail, it is to be understood that the terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims and equivalents thereof.

It is noted that, as used in this specification and the appended claims, the singular forms“a”,“an”, and“the” also include plural referents unless the context clearly dictates otherwise.

As used herein, the term“at least one” is to be interpreted as one or more.

The term“suspension” is intended to mean dispersion of a solid substance in a continuous phase, which is liquid at ambient temperature.

The term“pharmaceutical” is intended to mean in the context of the suspensions of the present invention, that the suspensions are in a form that can be used for treatment of intended diseases. This includes inter alia that the suspensions must fulfil the medical requirements of safety, and for a product for parenteral use this means the product must be sterile and manufactured under strict aseptic conditions if not possible to terminally sterilise.

The term“injectable” is intended to mean in this context a drug product, i.e. crystalline 3-alpha-hydroxy-5-alpha-pregnan-20-one in a suspension that is capable of being dispensed, using a needle with a defined inner needle diameter size (in other words capable of being ejected through the defined needle size) and not causing any significant blockage in the needle and that more or less the entire intended dose can be delivered through the needle. As used herein the present context, the term“more or less the entire intended dose” refers to at least about 80 %, such as at least about 90 %, or more of the entire dose. For example, said“more or less the entire intended dose” may mean at least 80 %, at least 81 %, at least 82 %, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88 %, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99 % or at least 100%.

As used herein, the term“recovery of dose” refers to the amount of the suspension which is injectable from a syringe, for example after storage of the syringe comprising the suspension. The recovery of dose may be estimated by e.g. measurement of volume, weight or content of the active ingredient.

The term“crystalline” is intended to mean highly ordered arrays of molecules held together by non-covalent interactions. The level or degree of crystallinity is at least 60%, or higher, wherein 100% represents that all material is crystalline. Quantification of crystallinity may be measured by X-ray powder diffraction methods or water vapor sorption measurements as described in Saleki-Gerhardt A et al. Int J Pharm. 1994; 101 :237-247.

The term“aseptic” or“aseptic conditions” is intended to mean conditions for a process that will result in a sterile product.

The term“sterile” in the context of the suspension as disclosed herein is intended to mean that upon specified tests according to the European pharmacopeia (e.g. Ph. Eur. 2.6.1 ) and/or corresponding regional

pharmacopeia in other territories (e.g. United States Pharmacopeia, USP) the suspensions of the present disclosure demonstrate no growth of bacteria or fungi or content of bacterial endotoxins.

The term“particles” is intended to mean, in the context of“crystalline, particles of a compound”, discrete crystals of said compound. For example, the term“particles” is intended to mean, in the context of “crystalline 3-alpha-hydroxy-5-alpha-pregnan-20-one particles”, discrete crystals of 3-alpha-hydroxy-5-alpha-pregnan-20-one.

The term“prefilled syringe” is intended to mean a medical syringe, which can be assembled with a needle or a syringe that is pre-equipped with a needle, which may be delivered to the patient prefilled with one or more doses of the final pharmaceutical composition, such as the suspension of the present invention. It is to be understood that the syringe may be injected by hand or by means of a device, such as an autoinjector.

The term“needle” is intended to mean a needle in this context for medicinal administration and includes standard needles of 20G diameter or thinner, such as 21 G, 22G, 23G, 24G, 25G, 26G, 27G, 28G, 29G or 30G diameter. G stands for gauge and is a measure used to define inner and outer diameters of needles. To exemplify this, a regular 25G needle has a nominal inner diameter of about 0.260 mm.

The terms“acylglycerol” and“mixture of acylglycerols" are intended to include all types and combinations of fatty acids esterified to glycerol. A mixture of acylglycerols can for instance consist of various mixtures of

monoacylglycerols, diacylglycerols and triacylglycerols. One example of a mixture of acylglycerols is represented by a medium-chain acylglycerol or consists or comprises medium-chain acylglycerol(s).

An example of a medium chain acylglycerol is medium chain triglyceride (MCT). MCT typically represents a mixture of triglycerides of saturated fatty acids including mainly caprylic acid (octanoic acid, C8H16O2) and capric acid (decanoic acid, C10H20O2), wherein the total combined percentage of fatty acids with 8 carbon atoms (octanoic acid) and 10 carbon atoms (decanoic acid) is at least about 95%. Medium-chain triglycerides may for example be obtained from the oil extracted from the hard, dried fraction of the endosperm of Cocos nucifera or from the dried endosperm of Elaeis guineensis in a process involving fractionation of the fatty acids, re-esterification and purification.

The mixture of acylglycerols may also be represented by a vegetable oil or consist or comprise vegetable oil(s). Thus, it can be a vegetable oil selected from the group consisting of sesame oil, peanut oil, olive oil, and castor oil, and mixtures of two or several thereof, such as the group consisting of sesame oil, peanut oil and olive oil and mixtures of two or several thereof, or mixtures thereof, such as sesame oil.

The mixture of acylglycerols can further comprise a mixture of a vegetable oil, such as one of the vegetable oils listed above, and medium-chain

acylglycerols.

The suspensions of the invention may comprise additional excipients known to a person skilled in the art such as antioxidants, preservatives, surfactants, colouring, or thickening agents.

As used herein, the term“ambient conditions” refers to non-controlled room temperature conditions. Ambient temperature is normally a temperature of about 18-25 °C, such as about 20°C, but may also be higher or lower due to the non-controlled nature thereof.

As used herein, the term“conditions wherein the temperature is cycled” refers to conditions wherein the temperature is cycled from refrigerated (about 2°C) to ambient (about 20°C) once every 24-hour period.

As used herein the term“refrigerated conditions” refers to a temperature of between about 2°C and about 10°C, such as between about 2°C and about 8°C, such as between about 4°C and about 8°C. By“physically stable” in the context of the present invention intends to mean that the suspension remains injectable through a needle, with the same or thinner inner diameter as used initially, after at least 6 months of storage with or without resuspending the suspension and with near full or full recovery of dose administered. To clarify, a physically stable suspension as disclosed herein is injectable through a needle, with the same or thinner inner diameter, at day 0 and after at least 6 months of storage.

As used herein the term“near full or full recovery to dose” refers to at least 80 %, such as at least 85 %, such as at least 87.5%, such as at least 90 %, such as at least 92.5%, such as at least 95%, such as at least 97.5%, or more of the entire dose (in other words intended dose). Preferable, the recovery of dose is close to 100 %, corresponding to the term“full recovery of dose” as used herein. The skilled person will appreciate, that it may not be possible due to accuracy of the filling volume, concentration and physical properties of the suspension, such as surface tension and viscosity, to recover the complete 100 % of the dose. In other words the term“full recovery of dose” is meant to be interpreted the close to 100 % of the complete content of the syringe is injectable from said syringe, such as 100% ± 20%, or such as 100% ± 15%, or such as 100% ± 10% or such as 100% ± 7.5%, or such as 100% ± 5%, or such as 100% ± 2.5 %.

As used herein, the term“homogeneous” in the context of a mixture or suspension refers to mixture or suspension that has the same proportions of its components throughout any given sample.

As used herein, the term“good fluidity” refers to the physical quality of suspension being fluid or free-flowing at ambient conditions.

The suspensions of the present invention are preferably administered parenterally for pharmaceutical use in therapeutically effective amounts to patients in need thereof. Typically, the suspension is provided by injection parenterally such as subcutaneously, intramuscularly, intracutaneously or intraperitonally, such as subcutaneously, intramuscularly or intraperitoneally. The suspensions of the invention may also be provided by topical, buccal, vaginal or rectal administration. The therapeutic use may be for prevention and/or treatment of conditions or disorders, for example epilepsy, depression, anorexia, anxiety disorders, premenstrual cycle related disorders, stress related disorders, migraine, Tourette’s syndrome, Fragile X syndrome and essential tremor and dementia and other disorders as listed below. The skilled person will appreciate that the formulation of the suspension may be adapted or adjusted according to normal pharmacological procedures, comprising the effective pharmaceutical in a chemical form suitable for the chosen route together with suitable adjuvants, carriers, diluents and vehicles, conventionally used and well-known to a person skilled in the art. Therefore, also encompassed by the present disclosure are pharmaceutical

compositions comprising the suspension as defined herein, further comprising at least one pharmaceutically acceptable carrier, excipient and/or diluent.

In one aspect of the invention, there is provided a pharmaceutical and physically stable suspension, comprising:

crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one; and a mixture of acylglycerols;

wherein the concentration of 3-alpha-hydroxy-5-alpha-pregnan-20-one is about 20 mg/mL, or higher.

In one embodiment of this abovementioned aspect, said suspension is sterile. In one embodiment of said aspect, said suspension is sterile and is prepared by mixing said components under aseptic conditions for about 36 hours or less, such as for about 30 hours or less, such as about 26 hours or less, such as preferably for about 24 hours or less. In particular embodiments, said mixing under aseptic conditions is performed for or less than for about 23, 22, 21 , 20, 19, 18, 17, 16, 15, 14, 13, 12, 11 , 10, 9, 8, 7, 6, 5, 4, 3, 2 or about 1 hours. It will be appreciated that a suspension as disclosed herein, prepared under aseptic conditions complying the previously mentioned guidelines of EMA (EMA/CHMP/CVMP/QWP/BWP/850374/2015), fulfills the requirements for a medicinal product and prepared under conditions that is acceptable for an industrial process.

In one embodiment, said suspension further comprises cholesterol. In one embodiment of this aspect, said suspension further comprises cholesterol at a concentration of about 0.1 % (w/w) or higher, such as about 1 % or higher. In one embodiment of the suspension as disclosed herein, said cholesterol is present at a concentration of about 3% (w/w) or lower, such as about 2.5% (w/w) or lower. Said cholesterol may be present at a concentration of approximately from about 0.1 to about 2.5% (w/w), such as from about 0.1 to about 2.0% (w/w), such as from about 0.5 to about 2.0% (w/w), such as from about 0.5 to about 1.5% (w/w) or such as from about 1 to about 2.5% (w/w) or from about 1 to about 2% (w/w). In one particular embodiment, said

cholesterol is present in the suspension at a concentration of approximately 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7,

1.8, 1.9, 2.0, 2.1 , 2.2, 2.3, 2.4 or approximately 2.5% (w/w). It may

furthermore be possible that the suspension comprises cholesterol at a higher concentration than 3% (w/w).

The concentration of 3-alpha-hydroxy-5-alpha-pregnan-20-one in the suspension as disclosed herein is about 20 mg/mL, or higher. For example said concentration of said 3-alpha-hydroxy-5-alpha-pregnan-20-one may be about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 mg/mL or higher. In one embodiment of the suspension as disclosed herein, the concentration of 3-alpha-hydroxy-5-alpha-pregnan-20-one is in the range of from about 20 mg/mL to about 100 mg/mL, such as from about 25 mg/mL to about 100 mg/mL, such as from about 50 mg/mL to about 100 mg/mL, such as from about 75 mg/mL to about 100 mg/mL.

In one embodiment of the suspension as disclosed herein, the concentration of 3-alpha-hydroxy-5-alpha-pregnan-20-one is in the range of from about 20 mg/mL to about 150 mg/mL, such as from about 25 mg/mL to about 150 mg/mL, such as from about 50 mg/mL to about 150 mg/mL, such as from about 75 mg/mL to about 150 mg/mL, such as from about 100 mg/mL to about 150 mg/mL.

In one embodiment of the suspension as disclosed herein, the concentration of 3-alpha-hydroxy-5-alpha-pregnan-20-one is in the range of from about 20 mg/mL to about 200 mg/mL, such as from about 25 mg/mL to about 200 mg/mL, such as from about 50 mg/mL to about 200 mg/mL, such as from about 75 mg/mL to about 200 mg/mL, such as from about 100 mg/mL to about 200 mg/mL, such as from about 125 mg/mL to about 200 mg/mL, such as from about 150 mg/mL to about 200 mg/mL. In one embodiment of the suspension as disclosed herein, the concentration of 3-alpha-hydroxy-5- alpha-pregnan-20-one is in the range of from about 20 mg/mL to about 75 mg/mL, for example from about 20 mg/mL to about 50 mg/mL or such as about 25 mg/mL to about 75 mg/mL, such as about 50 mg/mL to about 75 mg/mL. In one embodiment of this aspect, the concentration of said 3-alpha- hydroxy-5-alpha-pregnan-20-one is about 100 mg/mL, or higher, such as about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500 mg/mL, or higher. In one embodiment of the suspension as disclosed herein, the concentration of 3-alpha-hydroxy-5-alpha-pregnan-20- one is in the range of from about 100 mg/mL to about 500 mg/mL, such as about 100 mg/mL to about 400 mg/mL, such as about 100 mg/mL to about 300 mg/mL, such as about 100 mg/mL to about 200 mg/mL. For example, said concentration may be about 150 mg/mL to about 400 mg/mL, such as about 200 mg/mL to about 400 mg/mL, such as about 250 mg/mL to about 400 mg/mL, such as about 300 mg/mL to about 400 mg/mL; or about 100 mg/mL to about 350 mg/mL, such as about 150 mg/mL to about 350 mg/mL, such as about 200 mg/mL to about 350 mg/mL, such as about 250 mg/mL to about 350 mg/mL.

In one embodiment of this aspect, said suspension remains injectable after at least about 6 months, such as about 7 months, such as about 8 months, such as about 9 months, such as about 10 months, such as about 11 months, such as about 12 months of storage, or longer, for example about 24 months of storage, with full or near full recovery of dose.

In one embodiment, said“full or near full recovery of dose” corresponds to at least 80 %, such as at least 85 %, such as at least 87.5%, such as at least 90 %, such as at least 92.5%, such as at least 95%, such as at least 97.5%, or more of the entire dose.

In one embodiment, said full or near full recovery of dose corresponds to at least 80 %, such as at least 81 %, such as at least 82 %, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88 %, such as at least 89%, such as at least 90%, such as at least 91 %, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such at least 99 % or such at least 100% of the entire dose.

In one embodiment, said full or near full recovery of dose corresponds to 100% ± 20%, such as 100% ± 15%, such as 100% ± 10%, such as 100% ± 7.5%, such as 100% ± 5%, such as 100% ± 2.5 % of the entire dose.

For clarify, the entire dose as referred to herein is meant to be interpreted as the entire intended dose. For example in the event a syringe contains an amount of the suspension exceeding the intended dose (for example corresponding to several doses to be administered separately) each entire dose corresponds to the amount of suspension which is intended to be administered at each separate occasion.

In one embodiment, said storage is at ambient conditions, at conditions wherein the temperature is cycled, or at refrigerated conditions. It will be appreciated, that the recovery of full or near dose after storage allows to ensure that the intended dose is administered to the patient in need thereof and thus is of great importance for the treatment outcomes. In one embodiment of this aspect, said mixture of acylglycerols is represented by a medium-chain acylglycerol. In one embodiment of this aspect, said mixture of acylglycerols consists or comprises a medium-chain acylglycerol.

In one embodiment of this aspect, said medium-chain acylglycerol is or consists or comprises a medium chain triglyceride (MCT). In one

embodiment, said MCT is a mixture of triglycerides of saturated fatty, wherein the total combined percentage of octanoic acid and decanoic acid is at least about 95%, such as at least about 96%, such as at least about 97%, such as at least about 98%, such as at least about 99%, such about 100 %. In one embodiment, said MCT is from the oil extracted from Cocos nucifera or from Elaeis guineensis, or from both. In one embodiment of this aspect, said mixture of acylglycerols is represented by a vegetable oil, such as a vegetable oil selected from the group consisting of sesame oil, peanut oil, olive oil and castor oil and mixtures thereof; such as the group consisting of sesame oil, peanut oil and olive oil and mixtures thereof. In one embodiment of this aspect, said mixture of acylglycerols consists or comprises a vegetable oil, such as a vegetable oil selected from the group consisting of sesame oil, peanut oil, olive oil and castor oil and mixtures thereof; such as the group consisting of sesame oil, peanut oil and olive oil and mixtures thereof. It will be appreciated that said mixtures may comprise two or more of the above-mentioned oils. In one particular embodiment, said vegetable oil is sesame oil.

In yet another embodiment of this aspect, the mixture of acylglycerols consists or comprises a mixture of one or more vegetable oils and medium- chain acylglycerols. It will be understood that any of the vegetable oil and medium-chain acylglycerols mentioned above may be mixed, thus for example said mixture may be a mixture of sesame oil and MCT or a mixture of sesame oil, peanut oil and MCT. In one embodiment of this aspect, wherein said crystalline particles of 3- alpha-hydroxy-5-alpha-pregnan-20-one included in the suspension have an average particle size given as D50 of between about 0.5 and about 50 pm, for example between about 2 and about 25 pm. In one embodiment said average particle size given as D50 is between about 0.5 and about 25 pm, for example between about 2 and about 15 pm or between about 0.5 and about 15 pm or between about 0.5 and about 13 pm or between about 2 and about 13 pm. In one embodiment, said average particle size is measured in an aqueous phase.

For example, said average particle size given as D50 of said 3-alpha- hydroxy-5-alpha-pregnan-20-one particles may be from about 25 to about 18 pm or lower, such as from about 18 to about 10 pm or lower, such as from about 10 to about 7 pm or lower, such as from about 10 to about 5 pm or lower; such as from about 7 to about 3 pm or lower, such as from about 5 to about 2 pm or lower, such as from about 3 to about 1 pm or lower.

In one embodiment, said average particle size given as D50 of said 3-alpha- hydroxy-5-alpha-pregnan-20-one may be from about 2 to about 50 pm, such as from about 5 to about 50 pm, such as from about 7 to about 50 pm, such as from about 10 to about 50 pm; such as from about 2 to about 40 pm, such as from about 5 to about 40 pm, such as from about 7 to about 40 pm, such as from about 10 to about 40 pm; such as from about 2 to about 25 pm, such as from about 5 to about 25 pm, such as from about 7 to about 25 pm, such as from about 10 to about 25 pm; or may be from about 10 to about 50 pm, such as from about 20 to about 50 pm, such as from about 30 to about 50 pm; or may be from about 10 to about 40 pm, such as from about 20 to about 40 pm, such as from about 30 to about 40 pm; or may be from about 2 to about 20 pm, such as from about 5 to about 20 pm, such as from about 7 to about 20 pm, such as from about 10 to about 20 pm; or may be from about 2 to about 15 pm, such as from about 5 to about 15 pm, such as from about 7 to about 15 pm, such as from about 10 to about 15 pm; or may be from about 2 to about 13 pm, such as from about 5 to about 13 pm, such as from about 7 to about 13 pm, such as from about 10 to about 13 pm. In one embodiment, said crystalline particles of 3-alpha-hydroxy-5-alpha- pregnan-20-one have an average particle size given as D50 of about 2 pm or higher, such as about 5 pm or higher, such as about 7 pm or higher, such as about 10 pm or higher, such as about 13 pm or higher, such as about 15 pm or higher, such as about 25 pm or higher, such as about 50 pm. In one embodiment, said average particle size given as D50 of about 50 pm or less. In one embodiment, said average particle size is measured in an aqueous phase.

In one embodiment, said crystalline particles of 3-alpha-hydroxy-5-alpha- pregnan-20-one have a needle-like shape. In one embodiment of this aspect, wherein said crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one have an average width of from about 2 to about 15 pm and an average length of from about 20 to about 60 pm, such as an average width of from about 5 to about 10 pm and an average length of from about 25 to about 50 pm, such as an average width of from about 6 to about 8 pm and an average length of from about 30 to about 45 pm. In one embodiment, said average length and width is measured in an aqueous phase.

It is known in the art that particle size distributions can be estimate by e.g. laser diffraction. With this technique the particle size distribution of crystalline particles may be described with D values, typically the D10, D50 and D90 are commonly used values to represent the midpoint and range of the particle sizes of a given sample. The particle size distribution may be measured in water/aqueous phase or in an oil. The skilled person is familiar with such analyses, for example using equipment from Malvern Instruments.

In one embodiment of this aspect, said suspension is injectable through a 20G needle, or thinner, such as wherein the suspension is injectable through a 21 G, 22G, 23G, 24G, 25G, 26G, 27G, 28G, 29G or 30G needle. The skilled person is familiar with that the smaller gauge numbers indicate larger outer diameters of needles. Inner diameter depends on both gauge and wall thickness. The following chart shows nominal inner diameter and wall thickness for regular-wall 25G needles.

*mm in the table refers to millimeter.

Thin-wall needles have identical outer diameters but larger inner diameters for a given gauge. The skilled person is familiar with international standard for hypodermic needles ISO 6009:2016. To clarify, the gauges (G) used herein are according to ISO 6009:2016.

In one embodiment of this aspect, said suspension is for parenteral administration. In one embodiment, there is provided an injectable

suspension as disclosed herein, for clinical human parenteral use.

In one embodiment, said parenteral administration or use is selected from the group consisting of subcutaneous, intramuscular, intracutaneous and intraperitoneal administration or use, such as the group consisting of subcutaneous, intramuscular, and intraperitoneal administration or use, such as the group consisting of subcutaneous and intramuscular administration or use, such as wherein the parenteral administration or use is subcutaneous administration or use. It will be appreciated that administration routes which are suitable for self-administration may be preferred due to patient

convenience/compliance in some embodiments. For example, such routes may include subcutaneous injection. In another aspect of the invention, there is provided a pre-filled syringe equipped with a 20G needle, or thinner, comprising a suspension as disclosed herein. In one embodiment of this aspect, there is provided a pre- filled syringe equipped with a 20G needle, or thinner, comprising an injectable suspension as disclosed herein. In one embodiment of this aspect, said needle is a 21 G, 22G, 23G, 24G, 25G, 26G, 27G, 28G, 29G or 30G needle, or thinner; such as a 25G needle, or thinner, such as a 27 G needle or thinner.

Said prefilled syringe may be equipped with for example a 20G, 21 G, 22G, 23G, 24G, 25G, 26G, 27G, 28G, 29G or 30G needle. Said prefilled syringe may be arranged for a single administration only. Alternatively, the patient or health care professional may use the same prefilled syringe for several administrations and optionally exchange the needle between the

administration occasions.

In another aspect of the invention, there is provided a method of

manufacturing a suspension according to the invention, said method comprising the steps of

- sterilizing crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one, for example through irradiation, such as gamma irradiation and/or e-beam irradiation;

- optionally mixing a mixture of acylglycerols, preferably MCT, with

cholesterol and stirring until the cholesterol is completely dissolved in the mixture of acylglycerols;

- filtering the mixture of acylglycerols, optionally comprising cholesterol, and entering it aseptically into a sterile vessel and adding said sterilized crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one and mixing for about 36 hours or less, such as about 24 hours or less, to obtain a suspension; and

- filling the obtained suspension aseptically into sterile syringe barrels.

Said method may be described as a method of manufacturing a suspension as disclosed herein, wherein

- crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one are sterilized, for example through irradiation, such as gamma irradiation and/or e-beam irradiation; - a mixture of acylglycerols, preferably MCT, optionally is mixed with cholesterol and stirred until the cholesterol is completely dissolved in the mixture of acylglycerols;

- the mixture is filtered and entered aseptically into a sterile vessel and said sterilized crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan- 20-one are added and mixed for about 36 hours or less, such as about 24 hours or less; and

- the obtained suspension is optionally filled aseptically into sterile syringe barrels.

In one embodiment of said method of manufacturing, said sterilization is through gamma irradiation or e-beam irradiation. The skilled person is familiar with suitable sterilization methods.

Suspensions according to the invention may be manufactured as set out below:

Crystalline particles of said compound, such as 3-alpha-hydroxy-5-alpha- pregnan-20-one particles, in appropriate amount, are dispensed into a bag that can be sterilized via irradiation and is hence appropriate for aseptic manufacturing, such as a low density polyethylene (LDPE) bag, and sealed. The bag is sterilized via irradiation, such as through gamma irradiation or e- beam irradiation;

The mixture of acylglycerols, such as MCT, is optionally mixed with

cholesterol and stirred until the cholesterol is completely dissolved in the oil;

The acylglycerols mixture optionally comprising cholesterol is sterile filtrated, for example filtered via two 0.22 pm filters, and an appropriate amount of this sterile filtered acylglycerols mixture optionally comprising cholesterol is entered aseptically into a sterile compounding vessel in a clean room, such as a disposable compounding bag or a stainless-steel compounding vessel; The bag with the irradiated (sterilized) crystalline particles is adapted to the vessel, and the irradiated crystalline, particles of said compound, such as 3- alpha-hydroxy-5-alpha-pregnan-20-one particles, are added aseptically into the vessel. The sterilized crystalline particles of said compound, such as 3- alpha-hydroxy-5-alpha-pregnan-20-one particles, are then mixed with acylglycerols mixture optionally comprising cholesterol with a stirrer for efficient wetting of the powder and efficient mixing; continued for up to about 24 hours or less; and under gentle stirring, the suspension is filled aseptically into sterile syringe barrels (prefilled syringes) and thereafter the plungers (stoppers) are introduced.

The mixing of the sterile filtered mixture of acylglycerols mixture optionally comprising cholesterol and said sterilized particles of said compound, such as 3-alpha-hydroxy-5-alpha-pregnan-20-one particles, is carried out for about 36 hours or less, such as about 30 hours or less, such as about 26 hours or less, such as about 24 hours or less, such as for or less than for about 23, 22, 21 , 20, 19, 18, 17, 16, 15, 14, 13, 12, 11 , 10, 9, 8 or about 7 hours, or even for shorter times, such as about 6, 5, 4, 3, 2 or about 1 hours.

The crystalline particles of said compound, such as 3-alpha-hydroxy-5-alpha- pregnan-20-one particles, may be manufactured by methods omitting micronization steps. The term“micronization” as used herein, refers to a process with the intention to reduce the size of a solid material's particles, such as reduction of particle size to the micrometer or nanometer range, or under milder conditions break only larger particles and/or agglomerates of particles.

In one aspect of the invention, there is provided a suspension as disclosed herein, for use as a medicament.

It is envisioned that the suspension as disclosed herein may be useful for the treatment and/or prevention of a disorder, for example, epilepsy, status epilepticus, refractory status epilepticus, menstrual cycle dependent epilepsy, catamenial epilepsy, menstrual cycle related worsening of Petit Mai epilepsy, depression, major depression, stress related depression, post-partum depression, anorexia, anxiety disorders, premenstrual syndrome,

premenstrual dysphoric disorder, menstrual cycle linked mood changes, menstrual cycle related loss of impulse control, stress related mood changes, stress related loss of impulse control, post-traumatic stress disorder (PTSD), migraine, catamenial migraine, menstrual cycle linked migraine, stress related migraine, tiredness, stress related tiredness, hypersomnia, menstrual cycle linked hypersomnia, neuralgia, sedation, sleepiness, menstrual cycle linked sleep disorders, menstrual cycle linked balance disturbance, clumsiness, Tourette’s syndrome, involuntary movements, Fragile X syndrome and essential tremor, memory disturbance/disorder, stress related memory changes, Niemann-Pick-Disease, neuronal degenerative disorders, dementia, Alzheimer’s dementia (also referred to as Alzheimer’s disease) or menstrual cycle linked difficulties in concentration.

In one aspect of the invention, there is provided a suspension as disclosed herein, for use in treatment and/or prevention of a disorder, selected from the group consisting of: epilepsy, status epilepticus, refractory status epilepticus, menstrual cycle dependent epilepsy, catamenial epilepsy, menstrual cycle related worsening of Petit Mai epilepsy, depression, major depression, stress related depression, post-partum depression, anorexia, anxiety disorders, premenstrual syndrome, premenstrual dysphoric disorder, menstrual cycle linked mood changes, menstrual cycle related loss of impulse control, stress related mood changes, memory disturbance/disorder, stress related loss of impulse control, post-traumatic stress disorder (PTSD), migraine, catamenial migraine, menstrual cycle linked migraine, stress related migraine, stress related memory changes, menstrual cycle linked difficulties in concentration, neuronal degenerative disorders, tiredness, stress related tiredness, hypersomnia, menstrual cycle linked hypersomnia, sedation, sleepiness, menstrual cycle linked sleep disorders, neuralgia, menstrual cycle linked balance disturbance, clumsiness, Tourette’s syndrome, involuntary

movements, Fragile X syndrome, essential tremor, Niemann-Pick-Disease, dementia, and Alzheimer’s dementia; or the group consisting of epilepsy, status epilepticus, refractory status epilepticus, menstrual cycle dependent epilepsy, catamenial epilepsy, menstrual cycle related worsening of Petit Mai epilepsy, depression, major depression, stress related depression, post- partum depression, anorexia, anxiety disorders, premenstrual syndrome, premenstrual dysphoric disorder, menstrual cycle linked mood changes, menstrual cycle related loss of impulse control, stress related mood changes, stress related loss of impulse control, post-traumatic stress disorder (PTSD), migraine, catamenial migraine, menstrual cycle linked migraine, stress related migraine, memory disturbance/disorder, stress related memory changes, menstrual cycle linked difficulties in concentration, neuronal degenerative disorders, stress related tiredness, hypersomnia, menstrual cycle linked hypersomnia, menstrual cycle linked sleep disorders, neuralgia, menstrual cycle linked balance disturbance, Tourette’s syndrome, involuntary

movements, Fragile X syndrome, essential tremor, Niemann-Pick-Disease, dementia, and Alzheimer’s dementia.

In one embodiment said disorder is selected from the group consisting of epilepsy, status epilepticus, refractory status epilepticus, menstrual cycle dependent epilepsy, catamenial epilepsy, depression, major depression, stress related depression, post-partum depression, anorexia, anxiety disorders, premenstrual syndrome, premenstrual dysphoric disorder, stress related mood changes, stress related loss of impulse control, post-traumatic stress disorder (PTSD), migraine, catamenial migraine, menstrual cycle linked migraine, stress related migraine, memory disturbance/disorder, stress related memory changes, menstrual cycle linked difficulties in concentration, neuronal degenerative disorders, tiredness, stress related tiredness, hypersomnia, menstrual cycle linked hypersomnia, sedation, sleepiness, menstrual cycle linked sleep disorders, neuralgia, menstrual cycle linked balance disturbance, Tourette’s syndrome, involuntary movements, Fragile X syndrome, essential tremor, Niemann-Pick-Disease, dementia and Alzheimer’s dementia; the group consisting of epilepsy, status epilepticus, refractory status epilepticus, menstrual cycle dependent epilepsy, catamenial epilepsy, depression, major depression, stress related depression, post- partum depression, anorexia, anxiety disorders, premenstrual syndrome, premenstrual dysphoric disorder, stress related mood changes, stress related loss of impulse control, post-traumatic stress disorder (PTSD), migraine, catamenial migraine, menstrual cycle linked migraine, stress related migraine, memory disturbance/disorder, stress related memory changes, menstrual cycle linked difficulties in concentration, neuronal degenerative disorders, stress related tiredness, hypersomnia, menstrual cycle linked hypersomnia, menstrual cycle linked sleep disorders, neuralgia, menstrual cycle linked balance disturbance, Tourette’s syndrome, involuntary movements, Fragile X syndrome, essential tremor, Niemann-Pick-Disease, dementia and

Alzheimer’s dementia; or the group consisting of epilepsy, status epilepticus, refractory status epilepticus, menstrual cycle dependent epilepsy, catamenial epilepsy, depression, major depression, stress related depression, post- partum depression, anorexia, anxiety disorders, premenstrual syndrome, premenstrual dysphoric disorder, stress related mood changes, post- traumatic stress disorder (PTSD), migraine, catamenial migraine, menstrual cycle linked migraine, stress related migraine, memory disturbance/disorder, stress related memory changes, menstrual cycle linked difficulties in concentration, neuronal degenerative disorders, tiredness, stress related tiredness, hypersomnia, menstrual cycle linked hypersomnia, sedation, sleepiness, menstrual cycle linked sleep disorders, neuralgia, menstrual cycle linked balance disturbance, Tourette’s syndrome, involuntary movements, Fragile X syndrome, essential tremor, Niemann-Pick-Disease, dementia and Alzheimer’s dementia; or the group consisting of epilepsy, status epilepticus, refractory status epilepticus, menstrual cycle dependent epilepsy, catamenial epilepsy, depression, major depression, stress related depression, post- partum depression, anorexia, anxiety disorders, premenstrual syndrome, premenstrual dysphoric disorder, stress related mood changes, post- traumatic stress disorder (PTSD), migraine, catamenial migraine, menstrual cycle linked migraine, stress related migraine, memory disturbance/disorder, stress related memory changes, menstrual cycle linked difficulties in concentration, neuronal degenerative disorders, stress related tiredness, hypersomnia, menstrual cycle linked hypersomnia, menstrual cycle linked sleep disorders, neuralgia, menstrual cycle linked balance disturbance, Tourette’s syndrome, involuntary movements, Fragile X syndrome, essential tremor, Niemann-Pick-Disease, dementia and Alzheimer’s dementia; or the group consisting of epilepsy, status epilepticus, refractory status epilepticus, catamenial epilepsy, depression, major depression, stress related depression, post-partum depression, anxiety disorders, premenstrual syndrome, premenstrual dysphoric disorder, stress related mood changes, post- traumatic stress disorder (PTSD), migraine, menstrual cycle linked migraine, stress related migraine, neuronal degenerative disorders, tiredness, hypersomnia, menstrual cycle linked hypersomnia, sleepiness, neuralgia, menstrual cycle linked balance disturbance, Tourette’s syndrome, involuntary movements, Fragile X syndrome, essential tremor, Niemann-Pick-Disease, dementia and Alzheimer’s dementia; or the group consisting of epilepsy, status epilepticus, refractory status epilepticus, catamenial epilepsy, depression, major depression, stress related depression, post-partum depression, anxiety disorders, premenstrual syndrome, premenstrual dysphoric disorder, stress related mood changes, post-traumatic stress disorder (PTSD), migraine, menstrual cycle linked migraine, stress related migraine, neuronal degenerative disorders, hypersomnia, menstrual cycle linked hypersomnia, neuralgia, menstrual cycle linked balance disturbance, Tourette’s syndrome, involuntary movements, Fragile X syndrome, essential tremor, Niemann-Pick-Disease, dementia and Alzheimer’s dementia; or the group consisting of epilepsy, catamenial epilepsy, major depression, stress related depression, post-partum depression, anxiety disorders, premenstrual syndrome, premenstrual dysphoric disorder, post-traumatic stress disorder (PTSD), menstrual cycle linked migraine, stress related migraine,

hypersomnia, menstrual cycle linked hypersomnia, neuralgia, menstrual cycle linked balance disturbance, Tourette’s syndrome, Fragile X syndrome, essential tremor, and Niemann-Pick-Disease, dementia and Alzheimer’s dementia; or the group consisting of catamenial epilepsy, stress related depression, post-partum depression, premenstrual syndrome, premenstrual dysphoric disorder, post-traumatic stress disorder (PTSD), menstrual cycle linked migraine, stress related migraine, menstrual cycle linked hypersomnia, neuralgia, Tourette’s syndrome, Fragile X syndrome, essential tremor, Niemann-Pick-Disease and Alzheimer’s dementia.

In one particular embodiment, said disorder is selected from the disorders listed in groups 1 )-9) below, for example a disorder selected from group 1 ) consisting of epilepsy, status epilepticus, refractory status epilepticus, menstrual cycle dependent epilepsy, catamenial epilepsy and menstrual cycle related worsening of Petit Mai epilepsy; or a disorder selected from group 2) consisting of depression, major depression, stress related depression, post- partum depression and anxiety disorders; or a disorder selected from group 3) consisting of neuronal degenerative disorders, dementia, Alzheimer’s dementia and menstrual cycle linked difficulties in concentration, memory disturbances/disorders and stress related memory changes or consisting of neuronal degenerative disorders, dementia, Alzheimer’s dementia and menstrual cycle linked difficulties in concentration and stress related memory changes; or a disorder selected from group 4) consisting of premenstrual syndrome and premenstrual dysphoric disorder; or a disorder selected from group 5) consisting of post-traumatic stress disorder PTSD; or a disorder selected from group 6) consisting of migraine, catamenial migraine, menstrual cycle linked migraine, and stress related migraine; or a disorder selected from group 7) consisting of tiredness, stress related tiredness, hypersomnia, menstrual cycle linked hypersomnia, and menstrual cycle linked sleep disorders or consisting of stress related tiredness, hypersomnia, menstrual cycle linked hypersomnia, and menstrual cycle linked sleep disorders; or a disorder selected from group 8) consisting of menstrual cycle linked balance disturbance, clumsiness, Tourette’s syndrome and essential tremor; or a or consisting of menstrual cycle linked balance disturbance, Tourette’s syndrome and essential tremor; or adisorder selected from group 9) consisting of Fragile X syndrome and Niemann-Pick-Disease.

In one embodiment, said disorder is selected form the group consisting of post-partum depression, status epilepticus, refractory status epilepticus, Alzheimer’s dementia, memory disturbance/disorder, essential tremor, post- traumatic stress disorder (PTSD) and Niemann-Pick-Disease; such as the group consisting of post-partum depression, status epilepticus, refractory status epilepticus, Alzheimer’s dementia, memory disturbance/disorder, essential tremor and post-traumatic stress disorder (PTSD); such as the group consisting of post-partum depression, status epilepticus, refractory status epilepticus, Alzheimer’s dementia, memory disturbance/disorder and essential tremor; such as the group consisting of post-partum depression, status epilepticus, refractory status epilepticus, Alzheimer’s dementia, and memory disturbance/disorder; such as the group consisting of post-partum depression, status epilepticus, refractory status epilepticus and Alzheimer’s dementia; such as the group consisting of post-partum depression, status epilepticus and refractory status epilepticus; such as the group consisting of post-partum depression and status epilepticus; such as the group consisting of status epilepticus and refractory status epilepticus; such as the group consisting of post-partum depression and refractory status epilepticus. In one embodiment, said disorder is post-partum depression, status epilepticus or refractory status epilepticus.

For clarity, as used herein the term’’memory disturbance/disorder” refers to a condition that results of from alteration of neuroanatomical structures and/or neuronal function, which condition hinders the storage, retention and/or recollection of memories. Such memory disturbances/disorders may be progressive or immediate (for example due head injury) or degenerative disturbances/disorders. The memory disturbance/disorder referred to herein may be selected from memory disturbances/disorders associated with a condition selected from the group consisting of acquired brain injury, agnosia, amnesia, amnesia connected to traumatic brain injury, delirium, post surgical delirium, post traumatic delirium, dementia, Alzheimer’s disease, Down’s syndrome, hyperthymestic syndrome, Huntington’s disease, Parkinson’s disease, stress and Wernicke-Korsakoffs syndrome.

In a related aspect, there is provided a use of a suspension or

pharmaceutical composition as defined herein, for the manufacture of a medicament for the treatment and/or prevention of a disorder selected from any one of the groups defined above. The skilled person will appreciate that the disclosures relating to the previous aspects of the present invention are equally relevant to this present aspect and are not repeated here merely for the sake of brevity.

In a yet another related aspect, there is provided a method for treatment and/or prevention of a patient in need thereof, comprising administering to said patient a therapeutically effective dose of the suspension or

pharmaceutical composition as defined herein. Thus, there is provided a method of treatment and/or prevention of a disorder or disease as described herein, said method comprising the step of administering a therapeutically acceptable amount of a suspension or pharmaceutical composition described herein to a patient in need thereof. In one embodiment, said patient is suffering from or is at risk of suffering from any one of the disorders selected from any one of the group as defined above.

In one embodiment, said administration is parenteral administration, such as selected from the group consisting of subcutaneous, intramuscular, intracutaneous and intraperitoneal administration, such as the group consisting of subcutaneous, intramuscular, and intraperitoneal administration. The skilled person will appreciate that the disclosures relating to the previous aspects of the present invention are equally relevant to this present aspect and are not repeated here merely for the sake of brevity.

While the invention has been described with reference to various exemplary aspects and embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. Therefore, it is intended that the invention not be limited to any particular embodiment contemplated, but that the invention will include all embodiments falling within the scope of the appended claims. The invention will be further illustrated by the following non-limiting Examples.

Brief description of the figures

Figure 1 is a graphical illustration of the particle size distribution of crystals of 3-alpha-hydroxy-5-alpha-pregnan-20-one analyzed by Malvern Mastersizer according to Example 1.

Figure 2 is picture of a light microscopy image of crystals of 3-alpha-hydroxy- 5-alpha-pregnan-20-one in the suspension according to Example 4. One division in the graticule equals 10 pm.

Figure 3 is picture of a light microscopy image of crystals of 3-alpha-hydroxy- 5-alpha-pregnan-20-one in the suspension according to Example 7. One division in the graticule equals 10 pm.

Figure 4 shows the chemical structures of (A) 3-alpha-hydroxy-5-alpha- pregnan-20-one also known as allopregnanolone and (B) 3-beta-hydroxy-5- alpha-pregnan-20-one.

EXAMPLES

Example 1. Particle size distribution of 3-alpha-hvdroxy-5-alpha-preqnan-20- one determined using Malvern Mastersizer in aqueous phase.

The particle size distribution of a sample of 3-alpha-hydroxy-5-alpha-pregnan- 20-one was analyzed on a Malvern Mastersizer 3000. To 3.5 mg of 3-alpha- hydroxy-5-alpha-pregnan-20-one was added 0.35 mL of an aqueous 0.5% (weight/weight) solution of Tween 80 and the solution was sonicated for 30 seconds in a table sonicator. This solution was added to circulating water in the presentation unit of the Mastersizer. The particle size distribution was measured for 15 seconds using a Fraunhofer distribution model. The distribution curve according to Figure 1 demonstrated an average particle size of 13 pm (D50). D10 and D90 were demonstrated to be 5 and 38 pm, respectively.

Example 2. Solubility of 3-alpha-hvdroxy-5-alpha-preqnan-20-one in sesame oil

5.39 mg of 3-alpha-hydroxy-5-alpha-pregnan-20-one (CAS 516-54-1 , from Diosynth, Netherlands) was weighed out in a 4 ml_ vial with a fitting Teflon coated magnet and 1.237 g of sesame oil (Apoteket quality D) was added. After more than 24 hours stirring at ambient temperature the oil was clear, demonstrating a solubility of more than 4.4 mg per gram of sesame oil.

Additional 3-alpha-hydroxy-5-alpha-pregnan-20-one or sesame oil was added alternately with prolonged stirring. The solubility was estimated to 8 mg/g sesame oil (corresponding to 7 mg/mL).

Example 3. Solubility of 3-alpha-hvdroxy-5-alpha-preqnan-20-one in MCT with 1 % dissolved cholesterol.

1 % Cholesterol (Sigma) was dissolved in Medium Chain Triglycered (Captex 355, ABITEC corp., USA). 13.48 mg of 3-alpha-hydroxy-5-alpha-pregnan-20- one (as specified in Example 1 ) was weighed out in a 4 mL vial with a fitting Teflon coated magnet and 0.978 g of the MCT including 1 % cholesterol was added. After 48 hours stirring at ambient temperature there was still undissolved 3-alpha-hydroxy-5-alpha-pregnan-20-one, demonstrating a solubility of less than 13.8 mg per gram oil. Additional MCT oil was added which after stirring for 72 hours produced a clear oil. The solubility was thus estimated to 13 mg/g oil (corresponding to 12 mg/mL).

Example 4. Preparation of a 93 mq/mL suspension of 3-alpha-hvdroxy-5- alpha-preqnan-20-one in MCT with 1 % dissolved cholesterol. 65.1 mg of 3-alpha-hydroxy-5-alpha-pregnan-20-one was weighed out in a 4 ml_ glass vial with a fitting Teflon coated magnet. 0.616 g of MCT oil with 1 % dissolved cholesterol as described in Example 3 was added. After 5 minutes a visually good suspension was observed when the suspension was stirred at 500 rpm. Stirring was continued for 30 minutes under ambient temperature conditions to ensure that the oily phase was essentially saturated with 3- alpha-hydroxy-5-alpha-pregnan-20-one. The obtained suspension was homogeneous and had a good fluidity.

Light microscopy was made of the suspension obtained in on a Nikon microscope with a x10 objective provided with a Sagitta PC-camera inserted in one of the eye-pieces for recording of picture (Figure 2). For reference similar pictures are taken of a graticule, where one division equals 10 pm.

The majority of the crystals are slender needle-like crystals with typical dimensions 5-10 x 25-50 pm.

Example 5. Iniectability of a 93 mq/mL suspension of 3-alpha-hvdroxy-5- alpha-preqnan-20-one in MCT with 1 % cholesterol.

The injectability of the concentrated suspension obtained in Example 4 was investigated by expelling 0.56 g of the suspension in a 1 mL syringe (Terumo U-100 Insulin) through a fine needle (Fine-ject 27Gx1/2", Henke Sass Wolf, Germany). The suspension was easily ejected without any stop in the needle.

Example 6. Preparation of a 146 mq/mL suspension of 3-alpha-hvdroxy-5- alpha-preqnan-20-one in MCT

38.4 mg of 3-alpha-hydroxy-5-alpha-pregnan-20-one was weighed out in a 4 mL glass vial with a fitting Teflon coated magnet. MCT oil (Captex 355, ABITEC corp., USA) was added to a total weight of 254 mg. After 5 minutes a visually good suspension was observed when the suspension was stirred at 500 rpm. The obtained suspension was fluid and had a homogeneous appearance. Example 7. Microscopy of a 93 mq/mL suspension of 3-alpha-hvdroxy-5- alpha-preqnan-20-one in MCT

The suspension according to Example 6 was further diluted with the addition of 0.146 g of MCT so that the concentration of 3-alpha-hydroxy-5-alpha- pregnan-20-one is similar to that in Example 4. Stirring was continued for 30 minutes under ambient temperature conditions to ensure that the oily phase was essentially saturated with 3-alpha-hydroxy-5-alpha-pregnan-20-one. The obtained suspension was homogenous and had a good fluidity.

Light microscopy was made of the suspension as described in Example 4 (Figure 3). The majority of the crystals are slender needle-like crystals with typical dimensions of 5-10 x 25-50 pm.

Example 8. Testing iniectability of suspensions, comprising crystalline, 3- alpha-hvdroxy-5-alpha-preqnan-20-one according to the present invention.

In this Example, the injectability of suspensions of 3-alpha-hydroxy-5-alpha- pregnan-20-one in MCT with 1 % cholesterol was tested. Said suspensions include different amounts of crystalline 3-alpha-hydroxy-5-alpha-pregnan-20- one, and were prepared as described in the Example here below:

Suspensions comprising 3-alpha-hydroxy-5-alpha-pregnan-20-one in acylglycerol, and 1 % cholesterol, were prepared at concentrations of 100, 150, 200, 300, 400 and 500 mg/g, respectively, by intense mixing of crystalline 3-alpha-hydroxy-5-alpha-pregnan-20-one and MCT with 1 % added and dissolved cholesterol at 500 mg/g suspension for 30 minutes, followed by stepwise dilution to lower concentrations with MCT and 1 % cholesterol, to 400, 300 200, 150 and 100 mg 3-alpha-hydroxy-5-alpha- pregnan-20-one per g suspension. Injectability was evaluated after each dissolution step. The density is estimated to be to about 1 g/mL. Specifically, the density of the suspensions was estimated to a range of 0.95 to 1.1 g/ml, where the density increases with the concentration of 3-alpha-hydroxy-5- alpha-pregnan-20-one in the suspension. The viscosity of the suspensions increased with increased 3-alpha-hydroxy-5- alpha-pregnan-20-one concentration. Therefore, the suspensions with higher concentration of 3-alpha-hydroxy-5-alpha-pregnan-20-one required the use of a needle with a larger inner diameter in order to be injectable. The

suspension comprising 3-alpha-hydroxy-5-alpha-pregnan-20-one in MCT, and 1 % cholesterol at a concentration of 500 mg/g was paste-like, homogeneous and injectable with difficulty through a 20G needle with no stop. The suspension comprising 3-alpha-hydroxy-5-alpha-pregnan-20-one in MCT, and 1 % cholesterol at concentration of 400 mg/g was injectable with some difficulty through a 21 G needle with no stop. The suspension comprising 3- alpha-hydroxy-5-alpha-pregnan-20-one in acylglycerol, and 1 % cholesterol at concentrations of 200 mg/g and 300 mg/g, respectively, were injectable with some difficulty through a 23G needle with no stop. The suspension

comprising 3-alpha-hydroxy-5-alpha-pregnan-20-one in MCT, and 1 % cholesterol at concentration of 150 mg/g was injectable with some difficulty through a 25G needle with no stop. The suspension comprising 3-alpha- hydroxy-5-alpha-pregnan-20-one in MCT and 1 % cholesterol at concentration of 100 mg/g was injectable through a 25G needle with no stop and injectable with some difficulty through a 27G needle with no stop.

Example 9. Stability and iniectability of a suspension comprising crystalline, 3- alpha-hvdroxy-5-alpha-preqnan-20-one at 50 mq/mL in MCT with 1 % cholesterol.

A suspension prepared as described in Example 4 comprising 50 mg /ml_ 3- alpha-hydroxy-5-alpha-pregnan-20-one in MCT with 1 % cholesterol was made and filled in 0.4 ml_ syringes with a 27G needle.

Two sets of syringes were stored for six months. 6 syringes were stored vertically for six months and 6 syringes were stored horizontally for six months. Each syringes contained 0.4 ml_ suspension of 50 mg /ml_ 3-alpha- hydroxy-5-alpha-pregnan-20-one in MCT with 1 % cholesterol (see Table 1 and Table 2).The recovery of the full amount of the suspension (also referred to as full recovery of dose) was verified by visual inspection after emptying of a syringe through a 27G needle. The syringes were taken directly from storage and resuspended by turning the syringes 5 times before ejection as indicated in Tables 1 and 2. A subset of syringes were not resuspended.

Table 1. Six months stability of syringes stored vertically according to

Example 9. Each syringes contained 0.4 mL suspension of 50 mg /mL 3- alpha-hydroxy-5-alpha-pregnan-20-one in MCT with 1% cholesterol.

Table 2. Six months stability of syringes stored horizontally according to Example 9. Each syringes contained 0.4 mL suspension of 50 mg /mL 3- alpha-hydroxy-5-alpha-pregnan-20-one in MCT with 1% cholesterol.

Table 1 and 2 show that all syringes could be emptied after six months ambient storage with full or near full recovery of dose. Thus there were no stops in the needle, so the plunger reached the bottom of the syringe. This is the case even if the syringes are not turned 5 times before being emptied which was proposed as a method for resuspension. One vertically stored syringe was difficult to expel before resuspension, but could be expelled after resuspension. The variation in amount of suspension recovered can be explained by variations in filling of the syringes.

It is expected that all or near all of the suspension in the syringe is recovered (also referred to as full or near full recovery of dose) also after, 9 months and 12 months of storage in the syringe or longer storage in the syringe (such as up to 24 months, such as after up to 36 months of storage) and ejected through a 27G needle. Importantly, no apparent particle size change (or other change) which could affect injectability is expected to appear in the

suspension during the storage time. Thus, the storage of said suspension is expected not to affect the usefulness thereof in terms of injectability. Similar results are expected to be obtained when syringes are stored vertically and horizontally, at similar conditions with similar content.

Similar stability are also expected for suspensions with concentrations of 60 mg/mL or higher, such as 75 mg/mL, such as 96 mg/mL, such as 125 mg/mL, such as 200 mg/mL, such as 300 mg/mL, such as 400 mg/mL and such as 500 mg/mL.

Evaluation of injectability during the stability study should be performed using the same needle size. No stops were observed at the initial measurement at timepoint 0 of the stability study.

Example 10. Preparation of a 75 mg/mL suspension of 3-alpha-hvdroxy-5- alpha-preqnan-20-one in MCT with 0, 1 % and 2% dissolved cholesterol respectively.

3-alpha-hydroxy-5-alpha-pregnan-20-one was weighed out in a glass vial with a fitting Teflon coated magnet. MCT oil with 0, 1 and 2% dissolved

cholesterol, respectively was prepared as described in Example 3, and was added to the vial. The suspensions were prepared as described in Example 4. The obtained suspensions were homogenous and had a good fluidity.

The suspensions were stored in vials under cycled conditions where the temperature was cycled from refrigerated (about +2°C) to ambient (about +20°C) once every 24-hour period.

The injectability after 6 months of storage of the respective suspension was evaluated by aspiring 3 ml_ of the suspension into a syringe, attaching a G25, G27 or G30 needle to the syringe and passing the suspension through the needle. Each time an obstruction was observed, the needle is exchanged for a new needle, and the number of obstructions was recorded. Manual pressure is used to expel the suspension. Syringes used are: Luer-Lock Plastic Syringes, 3 ml_ (National Scientific Company. Rockwood, TN, USA) and the needles tested are G25x 5/8, G27x1/2 and G30x1/2 (Fine-ject, Henke Sass Wolf, Germany).

Injectability after 6 months cycled storage of a 75 mg/mL suspension of 3- alpha-hydroxy-5-alpha-pregnan-20-one in the MCT with 0, 1 and 2%

dissolved cholesterol, respectively, was tested. Number of injection stops, number of injection stops/gram suspension (stops/g) and total grams suspension tested (g tested) for the three different needles, G25, G27 and G30, respectively, are reported in Table 3.

Table 3: Injectability after 6 months cycled storage of a 75 mg/mL suspension of 3-alpha-hydroxy-5-alpha-pregnan-20-one in the MCT with 0, 1 and 2% dissolved cholesterol, respectively.

No injection stops were obtained for G25 and G27 needles after 6 months cycled storage for the suspensions according to the invention. The

injectability test of cycled suspensions with different cholesterol level showed that suspensions with no added cholesterol had a higher stop frequency in G30 needles (6.6 stops/g suspension) compared to suspensions with 1 % cholesterol (2.6 stops/g suspension) or 2 % added cholesterol (1.2 stops/g suspension). There were significantly more stops in the suspension without cholesterol, which shows that cholesterol stabilizes the suspended 3-alpha- hydroxy-5-alpha-pregnan-20-one in the MCT.

Example 11. Extended release of a suspension of 3-alpha-hvdroxy-5-alpha- preqnan-20-one when administered subcutaneously.

The pharmacokinetic profile of subcutaneously administered 3-alpha-hydroxy- 5-alpha-pregnan-20-one is studied in rabbits. Six White New Zeeland female rabbits (approximate body weight 3 kg) divided in two groups are given 1.5 mg/kg 3-alpha-hydroxy-5-alpha-pregnan-20-one either dissolved in MCT oil with 1 % cholesterol (3 mg/mL) or 3-alpha-hydroxy-5-alpha-pregnan-20-one suspended in MCT oil with 1 % cholesterol (30 mg/mL manufactured according to Example 4) and blood for determination of the plasma

concentrations of 3-alpha-hydroxy-5-alpha-pregnan-20-one is taken before administration and at timed intervals up to 72 hours post dose. The result is expected to show that the plasma concentration of 3-alpha-hydroxy-5-alpha- pregnan-20-one is elevated above baseline (before dosing) for a longer period following the administration of 3-alpha-hydroxy-5-alpha-pregnan-20- one when given in a suspension as compared to when the dose is given in a solution of 3-alpha-hydroxy-5-alpha-pregnan-20-one.

Thus, it is expected that suspension of 3-alpha-hydroxy-5-alpha-pregnan-20- one according to the invention will give an extended release and depot function when administered subcutaneously.

ITEMIZED LIST OF EMBODIMENTS

1. A pharmaceutical and physically stable suspension, comprising:

- crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one; and - a mixture of acylglycerols;

2. The suspension according to item 1 , wherein the concentration of 3- alpha-hydroxy-5-alpha-pregnan-20-one is about 25, 30, 35, 40, 45, 50,

55, 60, 65, 70, 75, 80, 85, 90, 95 mg/mL, or higher

3. The suspension according to item 1 or 2, wherein said suspension is sterile and prepared by mixing said components under aseptic conditions for about 36 hours, or less, such as for about 24 hours or less.

4. The suspension according to any one of items 1 -3, wherein said mixing under aseptic conditions is performed for less than about 23, 22, 21 , 20, 19, 18, 17, 16, 15, 14, 13, 12, 11 , 10, 9, 8, 7, 6, 5, 4, 3, 2 or about 1 hour(s).

5. The suspension according to any one of items 1 -4, further comprising cholesterol.

6. The suspension according to item 5, wherein said cholesterol is present at a concentration of about 0.1 % (w/w), or higher, such as about 1 %.

7. The suspension according to any one of items 5 and 6, wherein said cholesterol is present at a concentration of about 3.0% (w/w) or lower, such as about 2.5% (w/w), such as about 2.0% (w/w) or lower. 8. The suspension according to any one of items 1 -7, wherein the concentration of said 3-alpha-hydroxy-5-alpha-pregnan-20-one is about 100 mg/mL, or higher.

9. The suspension according to any one of items 1 -8, wherein the

concentration of said 3-alpha-hydroxy-5-alpha-pregnan-20-one is in the range from about 100 mg/mL to about 500 mg/mL, such as about 100 mg/mL to about 400 mg/mL, such as about 100 mg/mL to about 300 mg/mL.

10. The suspension according to any one of items 1 -9, wherein said

suspension remains injectable after at least about 6 months, such as about 7 months, such as about 8 months, such as about 9 months, such as about 10 months, such as about 11 months, such as about 12 months such as about 24 months such, as about 36 months of storage without resuspending the suspension and with full or near full recovery of dose.

11. The suspension according to item 10, wherein said storage is under conditions selected from storage at ambient conditions, storage at conditions wherein the temperature is cycled, and refrigerated

conditions.

12. The suspension according to any one of items 1 - 11 , wherein said

mixture of acylglycerols is represented by a medium-chain acylglycerol.

13. The suspension according to item 12, wherein said medium-chain

acylglycerol is a medium chain triglyceride (MCT).

14. The suspension according to item 13, wherein said MCT is a mixture of triglycerides of saturated fatty, wherein the total combined percentage of octanoic acid and decanoic acid is at least about 95%, such as at least about 96%, such as at least about 97%, such as at least about 98 %, such as at least about 99 %, such as about 100 %. 15. The suspension according to any one of items 1 - 11 , wherein said mixture of acylglycerols is a vegetable oil, such as a vegetable oil selected form the group consisting of sesame oil, peanut oil, olive oil, and castor oil and mixtures thereof, such as the group consisting of sesame oil, peanut oil and olive oil and mixtures thereof.

16. The suspension according to item 15, wherein said vegetable oil is

sesame oil.

17. The suspension according to any one of items 1 - 16, wherein said

mixture of acylglycerols comprise a mixture of a vegetable oil and medium-chain acylglycerols. 18. The suspension according to any one of items 1 -17, wherein said

crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one have an average particle size of about 5 pm, or higher.

19. The suspension according to any one of items 1 -18, wherein said

crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one have an average width of from about 2 to about 15 pm and an average length of from about 20 to about 60 pm, such as an average width of from about 5 to about 10 pm and an average length of from about 25 to about 50 pm. 20. The suspension according to any one of items 1 -19, wherein said

crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one have an average particle size in the range of from about 0.5 to about 50 pm, such as from about 2 to about 25 pm or wherein said crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one have an average particle size in the range of from about 0.5 to about 25 pm, such as from about 2 to about 15 pm.

21. The suspension according to any one of items 1 - 20, wherein said

suspension is injectable through a 20G needle, or thinner, such as wherein the suspension is injectable through a 21 G, 22G, 23G, 24G, 25G, 26G, 27G, 28G, 29G or 30G needle.

22. The suspension according to any one of items 1 - 21 , for parenteral administration.

23. The suspension according to item 22, wherein the parenteral

administration is selected from the group consisting of subcutaneous, intramuscular and intraperitoneal administration, such as the group consisting of subcutaneous and intramuscular administration.

24. The suspension according to item 23, wherein the parenteral

administration is subcutaneous administration.

25. A pre-filled syringe equipped with a 25G needle, or thinner, comprising a suspension according to any one of items 1 - 24.

26. Method of manufacturing a suspension according to any one of items 1 - 24, wherein

- crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one are sterilized, for example by irradiation, such as for example by gamma irradiation or e-beam irradiation;

- the mixture of acylglycerols, preferably MCT, optionally is mixed with cholesterol and stirred until the cholesterol is completely dissolved in the mixture of acylglycerols;

- the mixture of acylglycerols, optionally comprising cholesterol, is filtered and entered aseptically into a sterile vessel, said sterilized crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one are added and mixed for about 36 hours or less, such as about 24 hours or less; and

- the obtained suspension is filled aseptically into sterile syringe barrels.

27. A suspension according to any one of items 1 -24, for use as a

medicament. A suspension according to any one of items 1 -24, for use in the treatment and/or prevention of a disorder selected from the group consisting of epilepsy, status epilepticus, refractory status epilepticus, menstrual cycle dependent epilepsy, catamenial epilepsy, menstrual cycle related worsening of Petit Mai epilepsy, depression, major depression, stress related depression, post-partum depression, anorexia, anxiety disorders, premenstrual syndrome, premenstrual dysphoric disorder, menstrual cycle linked mood changes, menstrual cycle related loss of impulse control, stress related mood changes, stress related loss of impulse control, post-traumatic stress disorder (PTSD), migraine, catamenial migraine, menstrual cycle linked migraine, stress related migraine, memory disturbance/disorder, stress related memory changes, menstrual cycle linked difficulties in concentration, neuronal degenerative disorders, tiredness, stress related tiredness, hypersomnia, menstrual cycle linked hypersomnia, sedation, sleepiness, menstrual cycle linked sleep disorders, neuralgia, menstrual cycle linked balance disturbance, clumsiness, Tourette’s syndrome, involuntary movements, Fragile X syndrome, essential tremor, Niemann-Pick-Disease, dementia, and Alzheimer’s dementia. A method for treatment of a patient in need thereof, comprising administering to said patient a therapeutically effective dose of the suspension as defined any one of items 1 -24. Method for treatment according to item 29, wherein said patient is suffering from a disorder selected from the group consisting of epilepsy, status epilepticus, refractory status epilepticus, menstrual cycle dependent epilepsy, catamenial epilepsy, menstrual cycle related worsening of Petit Mai epilepsy, depression, major depression, stress related depression, post-partum depression, anorexia, anxiety disorders, premenstrual syndrome, premenstrual dysphoric disorder, menstrual cycle linked mood changes, menstrual cycle related loss of impulse control, stress related mood changes, stress related loss of impulse control, post-traumatic stress disorder (PTSD), migraine, catamenial migraine, menstrual cycle linked migraine, stress related migraine, memory disturbance/disorder, stress related memory changes, menstrual cycle linked difficulties in concentration, neuronal degenerative disorders, tiredness, stress related tiredness, hypersomnia, menstrual cycle linked hypersomnia, sedation, sleepiness, menstrual cycle linked sleep disorders, neuralgia, menstrual cycle linked balance disturbance, clumsiness, Tourette’s syndrome, involuntary movements, Fragile X syndrome, essential tremor, Niemann-Pick-Disease, dementia, and Alzheimer’s dementia. 31. Pharmaceutical composition comprising the suspension as defined according to any one of items 1 - 24, further comprising at least one pharmaceutically acceptable carrier, excipient and/or diluent.

Claims

1. A pharmaceutical and physically stable suspension, comprising:

2. The suspension according to claim 1 , wherein said suspension is sterile and prepared by mixing said components under aseptic conditions for about 36 hours or less, such as for about 24 hours or less.

3. The suspension according to claim 1 or 2, further comprising

cholesterol.

4. The suspension according to any one of claims 1 to 3, wherein the

concentration of said 3-alpha-hydroxy-5-alpha-pregnan-20-one is about 100 mg/mL, or higher.

5. The suspension according to any one of claims 1 to 4, wherein said suspension remains injectable after at least about 6 months of storage with or without resuspending the suspension and with full or near full recovery of dose.

6. The suspension according to any one of claims 1 to 5, wherein said mixture of acylglycerols is a medium-chain acylglycerol, such as a medium chain triglyceride (MCT).

7. The suspension according to any one of claims 1 to 5, wherein said mixture of acylglycerols is a vegetable oil, such as sesame oil.

8. The suspension according to any one of claims 1 to 8, wherein said crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one have an average particle size in the range of from about 0.5 to about 50 pm, such as from about 2 to about 25 pm, in an aqueous solution.

9. The suspension according to any one of claims 1 to 8, wherein said crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one have an average width of approximately from about 2 to about 15 pm and an average length of approximately from about 20 to about 60 pm, such as an average width of approximately from about 5 to about 10 pm and an average length of approximately from about 25 to about 50 pm.

10. The suspension according to any one of claims 1 to 9, wherein said suspension is injectable through a 20G needle, or thinner.

11. The suspension according to any one of claims 1 to 10, wherein said suspension is injectable through a 25G needle, or thinner.

12. The suspension according to any one of claims 1 to 11 , for parenteral administration.

13. The suspension according to claim 12, wherein the parenteral

administration is subcutaneous administration.

14. A pre-filled syringe equipped with a 25G needle, or thinner, comprising a suspension according to any one of claims 1 to 13.

15. Method of manufacturing a suspension according to any one of claims 1 to 13, wherein

- crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one are sterilized;

16. Method of manufacturing a suspension according to claim 15, wherein said crystalline particles of 3-alpha-hydroxy-5-alpha-pregnan-20-one are sterilized through irradiation.

17. Method of manufacturing a suspension according to claim 16, wherein said irradiation is gamma irradiation and/or e-beam irradiation.

18. A suspension according to any one of claims 1 to 13, for use as a medicament.

19. A suspension according to any one of claims 1 to 13, for use in the treatment and/or prevention of a disorder selected from the group consisting of epilepsy, status epilepticus, refractory status epilepticus, menstrual cycle dependent epilepsy, catamenial epilepsy, menstrual cycle related worsening of Petit Mai epilepsy, depression, major depression, stress related depression, post-partum depression, anorexia, anxiety disorders, premenstrual syndrome, premenstrual dysphoric disorder, menstrual cycle linked mood changes, menstrual cycle related loss of impulse control, stress related mood changes, stress related loss of impulse control, post-traumatic stress disorder (PTSD), migraine, catamenial migraine, menstrual cycle linked migraine, stress related migraine, memory disturbance/disorder, stress related memory changes, menstrual cycle linked difficulties in concentration, neuronal degenerative disorders, tiredness, stress related tiredness, hypersomnia, menstrual cycle linked hypersomnia, sedation, sleepiness, menstrual cycle linked sleep disorders, neuralgia, menstrual cycle linked balance disturbance, clumsiness, Tourette’s syndrome, involuntary movements, Fragile X syndrome, essential tremor, Niemann-Pick-Disease, dementia, and Alzheimer’s dementia.

20. Pharmaceutical composition comprising the suspension as defined according to any one of claims 1 - 13, further comprising at least one pharmaceutically acceptable carrier, excipient and/or diluent.