CZ20002207A3 - Pharmaceutical compositions comprising micronized bicyclic drugs - Google Patents

Abstract

A pharmaceutical composition comprising a compound of formula (I) in the form of particles, wherein said composition has a particle size distribution such that the mean particle diameter is in the range of 350 to 700 nm.

Description

Pharmaceutical compositions containing micronized bicyclic drugs

Technical field

The present invention relates to novel compositions containing compounds having therapeutic activity in particulate form, in particular compositions containing particles of poorly water-soluble compounds, wherein said compositions have improved bioavailability; and the use of such compositions in therapy.

State of the art

EP-A-0126311 and EP-A-0139992 describe benzpyran derivatives which have antihypertensive activity. WO 92/22293, WO 94/13657 and WO 95/34545 describe that benzpyran compounds also have anxiolytic and anticonvulsant activity and describe other benzpyran derivatives and related pyridopyran derivatives having similar activities. Unpublished International Patent Application No. PCT/EP97/05168 describes other uses of these compounds, including the treatment of neuropathic pain.

It is known to process pharmaceutically active compounds by milling to obtain particles of a suitable size for tableting and other types of formulations. Air jet milling and fluid bed milling (micronization) are preferred methods because they reduce the risk of contamination with the material used for milling. However, wet milling processes have been proposed for the preparation of finely divided particles for pharmaceutical use, see for example US-A-4540602 and EP-A-0499299. The latter application describes wet milling for the preparation of crystalline drug particles having adsorbed onto their surface a surface modifying agent in an amount sufficient to maintain an effective average particle size of less than 400 nm. This particulate formulation is reported to enable improved bioavailability for compounds with poor water solubility.

The essence of the invention

The present invention is based on the discovery that the benzopyran and pyridopyran compounds mentioned above have improved bioavailability in certain compositions formed of particles of controlled size. The present invention also includes a reproducible method for preparing such compositions.

The present invention therefore provides a composition comprising a compound of formula I or formula II as set forth below in the form of particles having a particle distribution such that the median particle diameter is in the range of 350 to 700 nm.

The compositions of the present invention may be in the form of an aqueous dispersion of particles of a compound of formula I or formula II; such compositions are typically prepared by a wet milling process. The compositions of the present invention may also be in the form of powders containing particles of a compound of formula I or formula II; such compositions are typically prepared by a spray drying or spray granulation process.

The compounds used in the present invention are as follows:

Formula I • · · · ·«»· «··« • · · β · · · * · · » »· ·«· · ♦ · · · « · · » · · » · Β · · · « · • · · · · · <· » b · · · · · where:

either Υ is Ν and R ₂ is hydrogen, or Y is CR _x ;

where:

one of R and R ₂ is hydrogen and the other is selected from the group consisting of the following groups: hydrogen, C ₃₈ cycloalkyl, C ₁₈ alkyl optionally interrupted by oxygen or substituted by a hydroxy group,

C alkoxy group or substituted with an aminocarbonyl group, C _e alkylcarbonyl, C _ig alkoxycarbonyl, C _is alkylcarbonyloxy, C _xe alkoxy, nitro, cyano, halogen, trifluoromethyl, CF ₃ S or a CF ₃ -A- group, where A is -CF^-, -CO-, -CHL,- or CH{OH), trifluoromethoxy, C _x _ ₆ alkylsulfinyl, _ _g alkylsulfonyl, C _xs alkoxysulfinyl, C _xg alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl, in which the aromatic group may be optionally substituted,

C _x _ ₆ Alkylcarbonylamino, C _x _ _g Alkoxycarbonylamino,

C _x _ _g alkyl-thiocarbonyl, C _x _ _g alkoxy-thiocarbonyl,

C _x _ _g alkylthiocarbonyloxy, 1-mercapto-C ₂₇ alkyl, formyl or aminosulfinyl, aminosulfonyl or aminocarbonyl, where any of the above groups may be optionally substituted with one or two C alkyl groups, or C _{x _ s} alkylaulfinylamino,

C _x _ _s alkylsulfonylamino, C _{x _ s} alkoxysulfinylamino or C x _{_ 6} alkoxysulfonylamino, or ethylenyl terminally substituted with groups selected from C _{i _ 6} alkylcarbonyl, nitro or cyano, or -C(C alkyl)NOH or -C(C alkyl)NNH, or one of R and R n is nitro, cyano or C ₃ alkylcarbonyl and the other is a methoxy group or an amino group optionally substituted with one or two C _x _ _s alkyl or C ₂₇ alkanoyl groups;

one of R and R is hydrogen or C alkyl and the other is C alkyl or R ₃ and R ₄ together are C _2s polymethylene;

R__ is C _is alkylcarbonyloxy, benzoyloxy, 0N0 ₂ , benzyloxy, phenyloxy »··· « · ♦ » · · » · • 9 · 4 9 44 4 «9 « • 9 Ο Λ · ·· · · · 4 6 6 • 9 9 4 6 4 4 4 4 4 6

6 4 4 4 4 6 6 4 ·· » · or C _1-6 alkoxy and R _g and R _s are hydrogen, or R_ is hydroxy and R _g is hydrogen or C alkyl and R _g is hydrogen;

R ₇ is fluorophenyl;

R ₅ is hydrogen or C ₁₅ alkyl;

The R _e -N-CO-R _v group is in the trans position with respect to the R _g group;

and X is oxygen or NR _xo , where R ₁₀ is hydrogen or C ₁₆ alkyl;

and

Formula II where:

either Y is N and R ₂ is hydrogen, or Y is CR _x ;

where:

one of R _x and R ₂ is hydrogen and the other is selected from the group consisting of the following groups: hydrogen, _{C 3-6} cycloalkyl, C ₁₁ alkyl optionally interrupted by oxygen or substituted by a hydroxy group,

C _x _ _with alkoxy group or substituted with aminocarbonyl group, C alkylcarbonyl, C _xe alkoxycarbonyl, C _x _ ₆ alkylcarbonyloxy,

C alkoxy, nitro, cyano, halogen, trifluoromethyl, CF S or the group CF -A-, where A is -CF,-, -CO-, -CH - or CH(OH), SO,, SO, CH ₂ -O or CONH, or the group CF^H-A'-, where A' is oxygen, sulfur,

SO, SO ₂ , CF ₂ or CHF; trifluoromethoxy, C _x _ _g alkylsulfinyl, perfluoro-C ₂ _ _g alkylsulfonyl, C _x _ _g alkylsulfonyl, C _x _ _g alkoxysulfinyl,

C _xg alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, • · · · * · ·· · » 99 • ♦ · » ··♦· »««· ··· » · · · · · · « * · * ♦ · · · · · · 4 · • ·» ··♦· · » · « ···· flfl ·· «β 99 «· heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl, in which the aromatic group may be optionally substituted, C _x _ _g alkylcarbonylamino,

C _x _ _s Alkoxycarbonylamino, C _x _ _g Alkyl-thiocarbonyl,

C _x _ _g alkoxy-thiocarbonyl, C _x _ _e alkylthiocarbonyloxy,

1-mercapto-C ₂ _ ₇ alkyl, formyl or aminosulfinyl, aminosulfonyl or aminocarbonyl, where any of the above groups may be optionally substituted with one or two C _xg alkyl groups, or C _x _ _g alkylaulfinylamino, C _xe alkylsulfonylamino, C _x _ _g alkoxysulfinylamino or C _xg alkoxysulfonylamino, or ethylenyl terminally substituted with groups selected from C _x _ _g alkylcarbonyl, nitro or cyano, or -C(C _xg alkyl)NOH or -C(C _xg alkyl)NNH ₂ , or one of R _x and R ₂ is nitro, cyano or C alkylcarbonyl and the other is a methoxy group or an amino group optionally substituted with one or two C alkyl or

C _{2-7 alkanoyl} groups; or R _x and R ₂ together form -(CH ) - or -CH=CH-CH=CH-, or form an optionally substituted triazole or oxadiazole ring;

one of R ₃ and R^ is hydrogen or C _x _ ₄ alkyl and the other is C _x _ ₄ alkyl, CF ₃ or CH ₂ X ^a , where X® ¹ is fluorine, chlorine, bromine, iodine, C _x _ ₄ alkoxy, hydroxy, C _{x _ 4} alkylcarbonyloxy, -SC _x _ 4 alkyl, nitro, amino optionally substituted with one or two C _x _ ₄ alkyl groups; cyano or C _x _ ₄ alkoxycarbonyl, or R ₃ and R ₄ together are C ₂ _ ₅ polymethylene optionally substituted with C _x _ ₄ alkyl;

^R 5 is C _1-6 alkylcarbonyloxy, benzoyloxy, ONO ₂ , benzyloxy, phenyloxy or C 1-6 alkoxy and R 5 and R 6 are hydrogen, or R 5 is hydroxy and R 6 is hydrogen or C _1-2 alkyl and R ₅ is hydrogen;

R^ is heteroaryl or phenyl; both of which are optionally substituted one or more times independently by a group or atom selected from the group consisting of: chlorine, fluorine, bromine, iodine, nitro, amino optionally substituted one or two times by _{C i_4} alkyl, cyano, azido, _{C x_4} alkyl, _{C x_4} alkoxy, trifluoromethoxy and trifluoromethyl;

R _e is hydrogen; C _{l 6} alkyl, OR _g or NHCOR _io , where R _s is hydrogen,

C _g alkyl, formyl, 0 _{χ β} alkanoyl, aroyl or aryl-C _{x 6} alkyl and R _io is hydrogen, C 10 alkyl, C ₁₀ alkoxy, mono- or di-C _{x ť} _alkylamino, amino, amino-C ₁₆ alkyl, hydroxy-C _xs alkyl, halo-C _xs alkyl,

C 10 acyloxy-C 10 alkyl, C 10 alkoxycarbonyl-C 10 alkyl, aryl or heteroaryl;

The R _e -N-CO-R _v group is in the cis position with respect to the R _s group;

and X is oxygen or NR _io , where R _io is hydrogen or C _{x <s} alkyl.

Compounds of formula I or formula II are described in EP-A-0139992, EP-A-0126311, WO 92/22293, WO 94/13657 and WO 95/34545. These publications containing information on the preparation and use of these compounds, on preferred substituents and the nature of substitution and on suitable individual compounds and methods for their preparation, are incorporated herein by reference.

Preferred compounds for use in the present invention are trans-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, hereinafter referred to as compound

I (for preparation see Example 20 of WO 92/22293); and cis-6-acetyl-4S-(3-chloro-4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3S-ol, hereinafter referred to as compound

II (for preparation see example 17 of WO 95/34545); and trans-6-acetyl-4S-(3,5-difluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol (for preparation see example 4 of WO 95/34545).

• ·· · · ·· · « · · * Φ · · t 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 Π • 9 9 9 9 9 9 9 9 9 9 9 9 9

The compounds used in the present invention have very poor water solubility. For example, Compound I has a water solubility of 0.008 mg/ml, which means that it is essentially insoluble according to USP classification.

The above compounds may be used in the form of pharmaceutically acceptable solvates, especially hydrates. They may be in crystalline or amorphous form prior to the milling process.

The compositions of the present invention are most preferably prepared by a wet milling process of the compounds of formula I and formula II in the form of an aqueous dispersion. For small scale production, wet milling is preferably carried out using a 2-chamber ball mill with material circulation between the chambers. To reduce contamination of the materials of the milling apparatus, the grinding medium is preferably rare earth oxide ceramic balls and the milling is carried out in chambers coated with or made of an abrasion resistant polymeric material such as nylon. For efficient milling, the balls in one chamber have a smaller diameter than the balls in the other chamber; satisfactory results can be achieved by using balls with a diameter of 1.25 mm in one chamber and balls with a diameter of 0.4 mm in the other chamber. The milling balls are preferably zirconium balls, especially balls made of yttrium-stabilized zirconium powder. For larger scale production, 5-chamber ball mills can be used. The material is processed in a single pass through one, two, three, four or all five chambers of the machine. For efficient grinding, the balls in the first chamber have a diameter of 0.65 mm to 1.25 mm. The balls in the other chambers have a smaller or the same diameter as in the previous mill.

To facilitate further processing, i.e. the preparation of pharmaceutical compositions for therapeutic use, such as tablets, injection dispersions, etc., the compounds of formula I and formula II are preferably wet-milled in an aqueous medium containing one or more additives, such as soluble carriers suitable for spray drying, surfactants designed to maintain the particles in suspension and anti-agglomeration agents effective after administration of the pharmaceutical composition to the patient. A particularly preferred additive for spray drying is mannitol, but other carbohydrates such as sorbitol, lactose, lactitol and xylitol and starch can also be used as carriers. Sodium lauryl sulfate is preferably used as surfactant and cellulose thickeners such as hydroxypropylmethylcellulose or hydroxyethylcellulose can be used as anti-agglomeration agents.

In the aqueous medium that is processed by milling, the compound of formula I or formula II may be present in an amount of from 10% to 30% (w/w). At 30% (w/w) and above, difficulties may arise in maintaining the suspension of the compounds of formula I or formula II during milling. In practice, 20% (w/w) is an effective compromise between high milling efficiency and short milling time.

The amount of soluble carrier may range from 4% to 15% (w/w) of the composition being processed by milling. Preferably, the amount of soluble carrier does not exceed 50% (w/w) of the amount of compound of formula I or II being processed. It has been found that for a compound constituting 20% (w/w) of the volume being processed, an amount of soluble carrier of from 4% to 10% (w/w) is effective, and a preferred amount of carrier is 5% (w/w).

The amount of surfactant ranges from 0.1% to 4% (w/w) of the aqueous medium. Preferably, the surfactant constitutes 1% by weight of the compound being treated.

The amount of anti-caking agent ranges from 1% to 2% « ·

I « • · • · • · (w/w) of the aqueous medium. Preferably, the anti-agglomeration agent constitutes 1.5% by weight.

The particles of the compounds of formula I and formula II are preferably uniformly distributed, with typically no more than 10% of the particles having a diameter of 280 nm or less and no less than 90% of the particles having a diameter of 2000 nm or less.

In a preferred embodiment of the invention, the median diameter of the particles is in the range of 400 to 600 nm, more preferably 450 to 550 nm. At this median diameter, compositions are obtained in which 10% of the particles have a diameter of 260 nm or less and 90% of the particles have a diameter of 1450 nm or less.

Using a bead milling system and an aqueous carrier, compositions having a preferred particle size distribution can be obtained surprisingly quickly, for example after milling for about 30 minutes when milling in low-capacity milling equipment using material recirculation. Increasing the milling time, for example to about 1 hour, allows the number of larger particles to be reduced so that at least 90% of the particles have a diameter of less than 1000 nm. However, the effect on the median diameter is negligible, so that longer milling times are not economically effective. Similarly, for large-scale processing, a batch of up to 200 kg with a compound content of about 20% can be processed surprisingly quickly and a preferred particle size distribution is obtained after a single pass of the material within 70 minutes.

The aqueous dispersion obtained by milling can be used directly as a therapeutic agent if prepared under suitable sterile conditions. Using water and other ingredients meeting Ph Eur standards, formulations can be obtained which can be stored for up to 1 month at 5°C without detectable bacterial growth. However, for the preparation of formulations suitable for human therapy, it is preferred that the aqueous dispersion be converted to a dry powder. This is best accomplished by spray drying, typically with the material being removed from the drying apparatus by means of a cyclone separator. Using the above additives in an aqueous milling medium yields a powder formulation containing the compounds of formula I or II in particulate form as a formulation with good flowability, suitable for use in a tablet formulation or in a powder for capsule preparation.

The compounds of formula I and II have hitherto been prepared in tablet form by first micronizing the drug substance and then wet granulating the micronized drug with tableting additives. The powder obtained by spray drying according to the present invention can be prepared in tablet form by direct compression. Surprisingly, it has been found that the milling time required to achieve the desired particle size distribution is essentially the same whether the starting material is micronized or not. The possibility of ball milling the non-micronized drug as obtained in the primary processing makes the present milling process economically advantageous. The wet material obtained in the processing is washed and dried and is then ready for milling. Alternatively, for some compounds it is possible for the wet material to be washed and resuspended, thereby making it ready for milling, which eliminates the costly drying step.

The compounds of formula I and II are believed to be useful in the treatment and/or prophylaxis of anxiety, mania, depression, panic disorder and/or aggression, diseases associated with subarachnoid hemorrhage or nervous shock, effects associated with withdrawal symptoms in addiction to cocaine, nicotine, alcohol and benzodiazepines, diseases treated with anticonvulsants, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia, obsessive-compulsive disorder (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (for example Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, in particular trigeminal neuralgia, neuropathic pain, toothache, tumor pain, inadequate neuronal activity resulting from neurodysaesthesia in diseases such as diabetes mellitus, multiple sclerosis (MS) and motor neuron diseases, ataxia, muscle rigidity (spasticity), temporomandibular joint dysfunction and/or amyotrophic lateral sclerosis (ALS). Administration of such compounds in particulate form to mammals can be accomplished by oral, parenteral, sublingual, nasal, pulmonary, rectal or transdermal routes.

The amount effective for treating the diseases described herein depends on usual factors such as the nature and severity of the disease being treated and the weight of the mammal. However, a dosage unit will usually contain 1 to 1000 mg, preferably 1 to 500 mg, for example 2 to 400 mg, for example 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of active compound. The dosage units are usually administered once or more times per day, for example 1, 2, 3, 4, 5 or 6 times per day, more often 1 to 4 times per day, so that the total daily dose is - for a 70 kg adult - in the range of 1 to 1000 mg, for example 5 to 500 mg, that is, the dose is in the range of about 0.01 to 15 mg/kg/day, more often from 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.

It is preferred that the compound of formula I be administered in unit dosage form, such as a unit dosage for oral, including sublingual, nasal, pulmonary, rectal, topical or parenteral (particularly intravenous) administration.

Such compositions are prepared by mixing and are suitably adapted for oral, parenteral or pulmonary administration and as such may be in the form of tablets, capsules, oral liquid compositions, powders, granules, cachets, reconstitutable powders, injectable and infusible solutions or suspensions or respirable powders or powder suspensions or suppositories. A suitable device for intrapulmonary administration is described, for example, in U.S. Pat. Patent Nos. 5,363,842, 5,392,768, 5,394,866, 5,404,871, 5,497,763, 5,509,404, 5,544,646, and 5,608,647. Oral formulations, especially shaped oral formulations, are preferred because they are most convenient for use.

Tablets and capsules for oral administration are usually prepared in unit dosage form and contain conventional additives such as binders, fillers, diluents, tabletting aids, glidants, disintegrants, colorants, flavorings, and wetting agents. The tablets may be coated by methods well known in the art.

Suitable fillers include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, cross-linked polyvinylpyrrolidone and other higher disintegrants and starch derivatives such as sodium starch glycolate. Suitable glidants include, for example, magnesium stearate.

Oral solid form compositions may be prepared by conventional methods of mixing, filling, tableting, and the like. Repeated mixing may be used to achieve uniform distribution of the active agent in those compositions which employ large amounts of fillers. Such techniques are, of course, known in the art.

Oral liquid compositions may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be prepared as dry preparations intended for reconstitution with water or other suitable vehicle before use.

·· ♦· ·* ·· «· ·· • · · * 9 · · · · · · · · • 99 9 9 99 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9 9

Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gels or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl-p-hydroxybenzoate or sorbic acid, and, if appropriate, conventional flavorings and colorings.

Oral formulations also include controlled-release formulations, such as tablets or granules provided with an enteric coating or other means to control the release of the active compound, for example, they may contain gel-forming polymers such as Methocel K4M.

For parenteral administration, liquid unit dosage forms are prepared containing the compound and a sterile vehicle. Parenteral suspensions are usually prepared by suspending the compound in a sterile vehicle, the compound having first been sterilized by exposure to ethylene oxide, gamma radiation, or other sterilization process. Alternatively, the entire process from recrystallization of the active compound, the solution of which has been previously sterilized by filtration, for example using a 0.22 micron membrane filter, may be carried out under aseptic conditions to ensure sterility. Preferably, the composition also contains a surfactant or wetting agent to facilitate homogeneous distribution of the compound of the present invention.

As is common, the device will also include written or printed • Φ *· ·· ·· ·· • · · · · · · · · · « • φφ φ · ·· « « · · • · · · · · φφφ · · · • φ φ φφ φ φ · « •ΦΦ ·* ·· ·· ·· instructions for use in the indicated treatment.

The present invention also includes a method for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorder and/or aggression, diseases associated with subarachnoid hemorrhage or nervous shock, conditions associated with withdrawal symptoms in addiction to cocaine, nicotine, alcohol and benzodiazepines, diseases treatable with anticonvulsants, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia, obsessive-compulsive disorder (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, in particular trigeminal neuralgia, neuropathic pain, toothache, tumor pain, inadequate neuronal activity resulting from neurodysaesthesia in diseases such as diabetes mellitus, multiple sclerosis (MS) and diseases motor neuron disease, ataxia, muscle rigidity (spasticity), temporomandibular joint dysfunction and/or amyotrophic lateral sclerosis (ALS), wherein an effective or prophylactic amount of a compound of the present invention is administered to a subject in need of such treatment.

In another aspect of the invention, the use of the composition according to the present invention for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorder and/or aggression, diseases associated with subarachnoid hemorrhage or nervous shock, conditions associated with withdrawal symptoms in addiction to cocaine, nicotine, alcohol and benzodiazepines, diseases treatable with anticonvulsants, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia, obsessive-compulsive disorder (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (for example Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, in particular trigeminal neuralgia, neuropathic pain, toothache, tumor pain, inadequate neuronal activity resulting from neurodysaesthesia in diseases such as diabetes mellitus, multiple sclerosis (MS) and motor neurone disease, ataxia, muscle rigidity (spasticity), temporomandibular joint dysfunction and/or amyotrophic lateral sclerosis (ALS).

A preferred process for producing small quantities of the particulate composition of the present invention may be carried out using a two-chamber ball mill, such as the laboratory-grade apparatus sold under the trade name DĚNA Mill by DĚNA Systems BK, Ltd., Mappledell, Barnsley, S75 6DT, with a grinding capacity of 2 litres. The mill comprises two reaction chambers SPS1, SPS2 and three different reaction vessels, D3, S1, SS. The mill can be operated in three different modes, mode 1, mode 2 and a combination of modes 1 and 2. Mode 1 uses the SPS1 reaction chamber which contains 1.25 mm balls. Mode 2 uses the SPS2 reaction chamber which contains 0.4 mm balls. When the machine is operated in a combination of modes 1 and 2, the suspension of the ground material passes through both reaction chambers.

The reaction chambers SPS1 and SPS2 contain rotating blades and both the reaction chamber and the rotating blades are made of inert, abrasion-resistant nylon. A screen of suitable size is placed inside the outlet of the reaction chamber to prevent the beads and any unground material from exiting the chamber. The speed of rotation of the blades is • 0

0· 0 0 00 000 constant.

Reaction vessels D3, S1 and SS carry out other processing. Reaction vessel D3 is a deagglomeration reactor; it is intended in particular for deagglomeration of the substance to be ground before entering the SPS1 reaction chamber. Reaction vessel S1 is a shear and emulsification reactor; it ensures that a uniform suspension is obtained at the end of the grinding. The SS reaction vessel is intended for homogenization of materials and emulsification of materials when it is desired to obtain a suspension before the grinding is completed. Suitable reaction vessels for mixing and homogenizing suspensions of solid materials are described in UK patent no. 2268090 B.

The interior of each reaction vessel has a honeycomb structure arranged to bend the flow in the reactor as determined by the reactor function. The mill also includes two heat exchangers; one for cooling the outlet of each reaction chamber.

When using this milling device in the present invention, the device is used according to the manufacturer's instructions for combined methods 1 and 2, so that the milled compound circulates between the two reaction chambers.

The grinding chambers were filled with YTZ ^R ceramic balls made of high-purity yttrium-stabilized zirconia powder (manufactured by Nikkato Corporation, Japan) as follows:

Ball Chamber

SPS1 Average

Density Hardness Weight

1.25 mm */_ 0.15 mm 6.07 g/cm ³ 12.6 Gpa 830 g

SPS1

Diameter

Density

Hardness

Weight

0.4 mm + 0.1 mm */_ 0.05 mm 6.07 g/cm ³ 12.5 Gpa 830 g

The milled suspension was spray dried using a Mobile Minor

Spray Dryer, manufactured by Niro Ltd., Denmark. In this apparatus, the aqueous suspension from the grinding equipment is introduced by a pump into the drying chamber in the form of an atomized spray. The dried powder passes into a cyclone separator, in which the resulting powder is separated.

The Mobil Minor device was used according to the manufacturer's instructions using the following settings:

Device settings: Atomizer speed approximately 25000 rpm

Suction fan/heater setting II Pump speed 40 rpm

Inlet temperature 140 °C

Outlet temperature 70 °C

Suspensions for milling in the apparatus described above were prepared from:

Compounds 1 SB Pharmaceuticals (in unground form, particle size typically 1 mm)

Compounds 2 SB Pharmaceuticals {in ground form, particle size typically 1 mm)

Mannitol from Roquette UK Ltd.

Hydroxypropyl methylcelluloses from Stancourt Sons and Muir

Sodium lauryl sulfate from Henkel Organics

The ratios of the compounds varied as indicated below.

Suspensions were prepared by dispersing r 4 4 4 4 4 4 4 4 ·· 4 • 44 4 444 4 44 4

4 444 44 444 44 4

44 4444 4444

4444 44 44 «4 44 44 hydroxypropylmethylcellulose (HPMC) in purified water, using a suitable mixing device. Mannitol was added to the hydroxypropylmethylcellulose dispersion followed by sodium lauryl sulfate. The test compound was then dispersed with high speed mixing and mixing was continued until no drug agglomerates were present.

Suspensions of the following composition were tested.

Component Specification Ratio % {wt/wt)

Measurement No. 1 2 3 4 5 6 Compound 1 SB Pharmaceuticals 20 15 10 20 30 40 specifications Mannitol Ph Eur 10 7.5 5 5 5 5 HPMC Ph Eur 1.5 1.5 1.5 1.5 1.5 1.5 Lauryl sulfate Ph Eur 0.2 0.2 0.1 0.2 0.3 0.4 sodium Purified Ph Eur 100 100 100 100 100 100

water to

After grinding the suspensions of compositions 1-6, the results are designated as D(0.1), D(G,5) and D(0.9). D(0.1) represents the size (average) of 10% of the particles, D(0.5) represents the size of 50% of the particles and is also referred to as the median.

D(0.9) denotes the size below which 90% of the particles fall. The particle size distribution is measured on a Malvern Mastersizer S laser diffraction unit from Malvern Instruments Ltd., Malvern, England.

Suspension

A suspension containing 10% (w/w) compound 1, 15% • ·* • · · · ·»·· >··· 9994 49 99 49 99 99 (w/w) compound 1, 20% (w/w) compound 1 (compositions 3, 2, 1) were milled sequentially, achieving suitable parameters of the resulting material within 60 minutes (see Tables 1, 2 and 3). It was found that a suspension containing 30% (w/w) (composition 5) could be produced in the form of a slurry, but the ball mill could process the slurry for only a few minutes before the second reaction chamber SPS2 (0.4 mm diameter balls) became blocked. 40% (w/w) slurry (composition 6) cannot be milled because it does not suspend sufficiently for transfer to the mill hopper.

Table 1

Time (minutes) Means D(0,l) m 1 D(0, 5) m D(0.9) m 0 ND ND ND (non-micronized drug) 60 0.24 0.40 0.71 120 0.27 0.39 0.56

ND - not specified

Table 2

Time (minutes) Method 2 D(0,l) m D(0.5) m D{0.9) m 0 0.53 10.21 73.06(micronized drug) 60 0.25 0.40 0.68 120 0.27 0.40 0.57

Φ· «φ φφ φφ »* «φ • Φ Φ Φ ΦΦΦΦ V φ 9 Φ • ·· · > Ί» ΦΦΦ Φ

ΦΦ ΦΦ* ΦΦ φφφ ΦΦ φ • ΦΦ ΦΦΦΦ Φφφ*

ΦΦΦΦ Φ« ΦΦ φφ φφ φφ

Table 3

Time (minutes) Method 3 D(0,l) m D(Q,5) m D(0.9) m 0 35.59 112.12 417.34 (non-micronized drug) 60 0.25 0.41 0.77 120 0.25 0.39 0.60

The milling of composition 1 was repeated with testing at shorter intervals as shown in Table 4. Comparison with Table 1 shows that the desired parameters were achieved between 45 and 60 minutes of milling.

Table 4

Time (minutes) Method 1 D(0,l) m D(0,5) m D(0.9) m 15 0.33 1.40 7.38 25 0.28 0.68 2.52 35 0.28 0.62 1.99 45 0.27 0.60 1.93

The suspension of composition 4 was milled for 70 minutes and samples were analyzed for particle size at 10 minute intervals (Table 5). As can be seen, the desired particle size was achieved after 30 minutes of milling. No further reduction in particle size was achieved during the additional 30 minutes of milling.

« « » · « · · * • 0 0 *· »» 00 ·4

Table 5

Time (minutes) Method 4 D(0,l) m D(0.5) m D(0.9) m 0 27.27 85.96 343.72 (non-micronized) 10 0.27 0.58 1.66 20 0.27 0.54 1.54 30 0.26 0.53 1.45 50 0.26 0.48 1.26 60 0.26 0.45 0.95 70 0.25 0.44 0.93

For all formulations with 5% or 10% mannitol content, spray drying was successful, as was repeated dispersion of the spray dried material.

To demonstrate that the described method is reproducible, six batches (A-F) of 20 kg suspension of composition 4 were milled in 2 kg sub-batches. 60 batches were milled and particle size analysis was performed on a 20 kg sample. In all six 20 kg batches, the desired particle size was achieved (Table 6) after 30 minutes of milling. The standard deviation for the three measurements is very low and shows no variation between batches.

(D(0,l) 4 x 10~ ³ ,

D(0.5) 5.5 x 10 ^-3 ,

D(0.9) 6 x 10" ³

99 • 9 9 9 • 9 9 r · 9

9 9

9999 99

ί. 9

9 ««

9· 9 9

Table 6

Means D(0,l) m D{0.5) m D(0.9) m 4A 0.27 0.49 1.03 4B 0.26 0.49 1.16 4C 0.26 0.50 1.23 4D 0.26 0.50 1.18 4E 0.26 0.50 1.21 4F 0.26 0.49 1.16

A preferred method for the commercial preparation of the composition of the present invention is to use a five-chamber ball mill, such as the commercial production apparatus sold under the name DĚNA DS1P5 Milli by DĚNA Systems BK, Ltd., Mapplewell, Barnsley, S75 6DT, with a milling capacity of 2 to 3 liters per minute. The mill consists of five reaction chambers SPS1 to SPS5 and seven different reactors (type D, S and SS). The mill operates in one mode, in which the ground material passes through each grinding chamber. Depending on the type of product, one to five grinding chambers may be used.

The reaction chambers SPS1 to SPSS and the reactors have a similar design to that in the small-scale milling plant described above.

The grinding chambers were filled with YTZ ^R ceramic balls made of high purity yttrium stabilized zirconia powder (manufactured by Nikkato Corporation, Japan) as follows. The diameter of the balls ranged from 0.3 mm to 1.25 mm. The ball volume in each chamber was from 6250 cc to 6750 cc.

• φ φ φ • φ φφφφ φφ

The milled suspension was spray dried using Niro Spray

Dryer, manufactured by Niro Ltd., Denmark. In this apparatus, the aqueous suspension from the grinding equipment is introduced by a pump into the drying chamber in the form of an atomized spray. The dried powder passes into a cyclone separator, in which the resulting powder is separated.

• φ • * ♦ φ « • φφφ φ φφφφ · • Φ φ *

The spray drying apparatus was operated according to the manufacturer's instructions using the following settings:

Device settings:

Atomizer speed

Pump speed Inlet temperature Outlet temperature

21000 to approximately 25000 rpm rpm 140 °C °C

Suspensions for milling in the apparatus described above were prepared from the same ingredients and active compounds as described above for small-scale production:

Suspensions of the following composition were tested.

Component Specification Ratio % (w/w)

Means No. 1

Compound 1

Mannitol

HPMC

Sodium Lauryl Sulfate

Purified water into

SB Pharmaceuticals specifications Ph Eur Ph Eur Ph Eur

Ph Eur

1.5

0.2

100

4

4 *044 44 * 4

4 « • 4 4 4 • 4 4 4 4

4 4 9 « » «4 > Λ * · 4 4

4 4 · • 4 4 «

4 *ι * *4 »4

After grinding suspensions of composition 1 using different ball fillings and different ball sizes, the results shown in Table 7 as D(0.1), D(0.5) and D(0.9) are obtained. D(0.1) represents the size (average) of 10% of the particles, D(0.5) represents the size of 50% of the particles, also referred to as the median. D(0.9) represents the size below which 90% of the particles fall.

The particle size distribution is measured on a Malvern Mastersizer S laser diffraction unit from Malvern Instruments Ltd., Malvern, England.

Table 7

Number of grindings Means 1

chamber D<0,l) m D(0.5) m D(0.9) m 0 36 112 417 (non-micronized drug) 1 0.25 to 0.46 2.4 to 4.2 10.3 to ; 18 2 0.32 to 0.34 1.1 to 1.3 5.0 to 6.5 3 0.29 to 0.30 0.71 to 0.87 2.8 to 4.5 4 0.25 to 0.30 0.54 to 0.81 1.4 to 2.1 5 0.25 to 0.28 0.48 to 0.52 1.0 to 1.3

Yttrium and zirconium concentrations in all milled suspensions were tested using inductively coupled plasma analysis and were found to be at acceptable levels. Iron concentrations were also low. Acceptable levels of zirconium and yttrium were considered to be less than 200 ppm Zr and less than 20 ppm yttrium in the spray-dried powder. The results show that the beads do not disintegrate during milling and the nylon grinding chambers are not damaged by the beads.

Φ Φ φφ φ · · φ φ φφ • In Φ φφφ φφφφ φ· φ φ

or suspension.

Bioequivalence testing ♦ · ·» φ · φ φ φ φφφ φ φφφ φ φ φ φ φφ φ φ

Bioequivalence testing was conducted on four healthy volunteers to determine the bioavailability of four oral formulations of Compound I. The study was open-label, randomized, crossover. Each subject was administered, randomly, on different days, 400 mg of each of the four different formulations of Compound I orally in a single dose. Compound I was administered orally in tablet or capsule form, and on each of the four dosing days, the subjects were administered single oral doses of Compound I, with a break of at least 6 days between doses. For each subject, the four formulations were administered randomly on each of the four study days. The doses were administered orally with 200 ml of water, after a normal breakfast. The spray-dried material resulting from the suspension of Formulation 4 was compressed into a tablet by direct compression.

The control tablet contained the following ingredients:

Ingredient mg/tablet Compound I (micronized) 400.00 Sodium starch glycolate 24.00 Microcrystalline cellulose Ph. EUR 23.28 Polyvinylpyrrolidone USP 9.60 Sodium Lauryl Sulfate BP 2.40 Lactose (monohydrate) Ph. Eur. 18.48 Magnesium stearate Ph. Eur. 2.40 Purified water Ph. Eur. q. .s. (removed during processing)

Total tablet weight 480.16

The test conditions were the same for both products. Results ·

(Tables 10 and 11) show an approximately 3-fold increase in blood concentration of Compound I when administered in a tablet prepared from formulation 4 compared to a tablet prepared from micronized drug.

» ”» » W »4 · φ • 4· · · 44 « * · · ® · · · > · » • ·* · · · 4 φ ···♦ 99 «4 ,·

Table 10

Control tablet Wet-milled tablet spray-dried AUC (mg.hr/ml) 11, 8 31.5 C (mg/ml) 1.07 3.03 T (h) 3.8 3.3 max

AUC - area under the curve

Cmax - maximum plasma concentration

T - time of maximum plasma concentration msiac

Table 11: Results of the bioequivalence study

Time (hrs) Control tablet Wet-milled spray-dried tablet (plasma concentration g/ml)

0 0.00 0.00 0.48 0.20 0.20 1.0 0.35 0.65 1.5 0.50 1.30 2.0 0.70 2.40 3.0 1.00 2.75 4.0 0.95 3.00 6, 0 0.90 2.30 8.0 0.69 1.75 10.0 0.65 1.50 12.0 0.60 1.30 24.0 0.50 0.80

Maximal electroshock-evoked twitch threshold test (MEST) ♦ · • φ • · · · in rats

Further details are given in Upton et al., (1997, Br. J.

Pharmacol., 121: 1679-1686).

The threshold for electroshock-induced tonic contractions of the extensors of the hindlimbs in male rats (Sprague-Dawley strain, 70-130 g) was determined using a Hugo Sachs Electronic stimulator, which applied a constant current (0.3 s duration, alternating current, fully adjustable from 1 to 300 mA) through corneal electrodes. The stimulus intensity was varied (from the usual baseline current of 25 mA) up-and-down by the shock titration method using a current change of 5-20 mA. Hindlimb extension was recorded as present or absent. Data obtained from experimental groups of 10-14 rats were used to calculate the CC _so value (current producing maximal contractions in 50% of the animals + SEM according to the method described by Kimball et al., (1957, Radiation Res.

7: 1-12). The effect of the various drugs was expressed as the % change in CC 50 _compared to vehicle-only controls. An increase in seizure threshold indicates an anticonvulsant effect. Significant effects (p > 0.05) of the drug on the seizure threshold induced by maximal electroshock were determined by comparing the ratios of CC ₅₀ values for drug or vehicle groups using the method described by Litchfield and Wilcoxan (1949, J. Pharmacol. Exp. Ther. 96: 99-113).

Test drugs were administered orally using a volume of 1 ml/kg.

• * φ φ

Anticonvulsant effects of various formulations containing compound 2 (5 mg/kg p.o.) in the MEST test in rats

Pre-test. % increase in threshold Medium 4 ^d time (min.) 1% methyl- cellulose micronized compound ground wet milled compound ^c compound® wet + SLS ¹ * 15 76 114 181 182 184 30 202 231 369 335 410 60 194 369 444 424 492 90 — 549 557 410 580 120 576 798 526 839 893 15 minutes/ 11% 14% 34% 22% 21% 2 hours

Conclusions: 1. c and d have a better overall effect than a

2. b, c and d have a faster onset of action than a

Claims (22)

Patent claims What is claimed is: 1. A pharmaceutical composition comprising a compound of formula I or formula II as follows, in the form of particles, said composition having a particle size distribution such that the average particle diameter is in the range of 350 to 700 nm, wherein the compounds formulas I and II are as follows: wherein either Y is N and R ₂ is hydrogen, or Y is CR 6 wherein: one of R and R ₂ is hydrogen and the other is selected from the group consisting of a hydrogen atom, C ₃ _ ₈ cycloalkyl, C ^ alkyl optionally interrupted by oxygen or substituted by hydroxy, C-L-alkoxy or substituted aminocarbonyl, C ₁ _ ₆ alkylcarbonyl, C ^ .galkoxykarbonyl, Ci galkylkarbonyloxy C- _g _ _L alkoxy, nitro, cyano, halogen, trifluoromethyl, CF ₃ S, or a group CF ₃ -A ', where A is -CF ₂ ~ -CO-, -CH ₂ - or CH (OH), trifluoromethoxy, C ₁ _ ₆ alkylsulphinyl, C ₁ _ _g alkylsulfonyl, C ₁ _ _g alkoxysulfinyl, C ₁ _ _g alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, arylsulphinyl, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl in which any aromatic moiety is optionally substituted, C ₁ _ _g alkylcarbonylamino, C ₁ _ _g alkoxycarbonylamino, C ₁ _ _g alkyl-thiocarbonyl, C ^ alkoxy-thiocarbonyl, C ₁ _ _g alkyl thiokarbonyloxy l mercapto-C ₂ _ ₇ alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, any of which • • · · · • 4 »· 4 94 4 ·· above groups may optionally be substituted by one or two C ₁ _ _g alkyl groups, or C ₁ _ _g alkylsulfinylamino, C galkylsulfonylamino, C or C galkoxysulfinylamino galkoxysulfonylamino, or ethylenyl terminally substituted by groups selected from C ₁ _ _g alkylcarbonyl, nitro or cyano, or -C (C ₁ _ _g alkyl) NOH or -C (C ₁ _ _g alkyl) NNH _2, or one of R and R ₂ are nitro, cyano or C ₁ _ ₃ alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C galkylovými or C ₂ _ ₇ alkanoyl groups; one of R ₃ and R ₄ is hydrogen or C ₁ _ ₄ alkyl and the other is C ₁ _ ₄ alkyl or R ₃ and R ₄ together C ₂ _ ₅ polymethylene; R ₅ is C ₁ _ _g alkylcarbonyloxy, benzoyloxy, ONO _2, benzyloxy, phenoxy or _C1-g alkoxy and _Rg and Rg are hydrogen or _Rg is hydroxy and R _g is hydrogen or C ₁ _ ₂ alkyl and R _g is hydrogen; R _? is fluorophenyl; R ₈ is hydrogen or C _L _ _g alkyl; _{Rg-N-CO-R 7} group is in the trans position relative to R ₅ group; and X is oxygen or NR _10, wherein R _Q1 is hydrogen or C ₁ _ _alkyl; II • φφ φ φ φ where: either Y is N and ₂ is hydrogen, or Y is C-R₁, · wherein: one for R ₂ is hydrogen and the other is selected from the group consisting of a hydrogen atom, C ₃ _ ₈ cycloalkyl, C ₁ _ ₆ alkyl optionally interrupted by oxygen or substituted by hydroxy, Cg ^ .galkoxyskupinou or substituted aminocarbonyl, C ^ alkylcarbonyl, C ₁ _ ₆ alkoxycarbonyl, Ci galkylkarbonyloxy, C ₁ _ ₆ alkoxy, nitro, cyano, halogen, trifluoromethyl, CF ₃ S, or a group CFG-A-, where A is -CF ₂ ~ -C0-, -CH ₂ - or CH (OH), SO ₂ , SO, CH ₂ -O or CONH, or CF ₂ H-A'-, wherein A 'is oxygen, sulfur, SO, S0 _2, CF _2, or CHF; trifluoromethoxy, Cj.galkylsulfinyl, perfluoro-C ₂ _ ₆ alkylsulphonyl, C ^ alkylsulphonyl, C ₁ _ ₆ alkoxysulfinyl, CL-galkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylkarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl in which any aromatic moiety is optionally substituted, C ₁ _ ₆ alkylcarbonylamino, C ₁ _ ₆ alkoxycarbonylamino, C ₁ _ ₆ alkyl-thiocarbonyl, C ^ .galkoxy-thiocarbonyl, Ci galkythiokarbonyloxy l-mercapto-C ₂ _ ₇ alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, wherein any of the above groups optionally substituted by one or two C ^ .galkylovými groups, or a C ₃ _ ₆ alkylaulfinylamino, C ₁ _ ₆ alkylsulphonylamino, C ₁ _ ₆ alkoxysulfinylamino or C ₁ _ ₆ alkoxysulfonylamino, or ethylenyl terminally substituted by groups selected from C ₁ _ ₆ alkylcarbonyl, nitro or cyano or -C (C ₁ _ ₆ alkyl) NOH or -C (C ₁ _ ₆ alkyl) NNH _2, or one of R ₁ and R ₂ are nitro, cyano or C ₁ _ ₃ alkylcarbonyl and the other is methoxy or amino optionally and substituted by one or two C ₁ _ ₆ alkyl or C ₂ _ ₇ alkanoyl groups; or R 1 and R ₂ together form - (CH ₂ ) ₄ - or -CH = CH-CH = CH-, or form an optionally substituted triazole or oxadiazole ring; • * • ···· ·· · • * · · · · · ·· «· one of R ₃ and R ₄ is hydrogen or C ₁ _ ₄ alkyl and the other is C ₁ _ ₄ alkyl, CF ₃ or CH ₂ X ^and wherein X ^is fluoro, chloro, bromo, iodo, C ₁ _ ₄ alkoxy, hydroxy, C ₁ _ ₄ alkylcarbonyloxy, -SC ₁ _ ₄ alkyl, nitro, amino optionally substituted by one or two C ₁ _ ₄ alkyl groups; cyano or C ₁ _ ₄ alkoxycarbonyl, or R ₃ and R ₄ together C ₂ _ ₅ polymethylene optionally substituted by C ₁ _ ₄ alkyl; ^R 5 ³ and C ₁ _ ₆ alkylcarbonyloxy, benzoyloxy, 0N0 _2, benzyloxy, phenoxy or C ₁ _ ₆ alkoxy and Rg and _Rg are hydrogen or _R5 is hydroxy and Rg is hydrogen or C ₁ _ ₂ alkyl and R ₉ is hydrogen; R ₇ is heteroaryl or phenyl; wherein both are optionally substituted one or more times independently with a group or atom selected from the group consisting of; chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by C ₁ _ ₄ alkyl, cyano, azido, C ₁ _ ₄ alkyl, C ₁ _ ₄ alkoxy, trifluoromethoxy and trifluoromethyl; R ₈ is hydrogen; C- ^ alkyl, 0R _g or NHCOR ₁₀ wherein R _g is hydrogen, C alkyl, formyl, C ^ .galkanoyl, aroyl or aryl-C ₁ _ ₆ alkyl and R ₁₀ is hydrogen, C ₁ _galkyl, C ₁ _ ₆ alkoxy, mono- or di-C ₁ _galkylamino, amino, amino-C ^^. alkyl, hydroxy-C ₁ _ ₆ alkyl, halo-C ^ alkyl, C gacyloxy-C alkyl, C ₁ -C ₁ _galkoxykarbonyl C _1-6 alkyl, aryl or heteroaryl; Rg-N-CO-R ₇ group is in the cis position relative to R ₅ group; and X is oxygen or NR ₁₀ wherein R ₁₀ is hydrogen or C ₁ _ ₆ alkyl. Composition according to claim 1, characterized in that the particles of the compounds of formula I or formula II are present in uniform distribution. • ··· · · ·· ·· ·· ·· The composition of claim 2, wherein no more than 10% of the particles have a volume diameter of 280 nm or less and no less than 90% of the particles have a volume diameter of 2000 nm or less. Composition according to any one of claims 1 to 3, characterized in that the mean volume diameter is in the range of 450 to 550 nm. The composition of claim 4, wherein not 10% of the particles have a volume diameter of 260 nm or less and 90% of the particles have a volume diameter of 1450 nm or less. Composition according to any one of claims 1 to 6, characterized in that it is obtainable by wet grinding the compounds of formula I and formula II in the form of an aqueous dispersion. A composition according to claim 6, which is obtainable by wet grinding using a multi-chamber ball grinding machine with a single material passage or material recirculation between the chambers. A composition according to claim 6 or 7, which is obtainable using a rare-earth oxide ceramic ball as a grinding medium. A composition according to claim 7 or 8, characterized in that it is obtainable using a multi-chamber grinding machine in which the balls in one chamber have a smaller diameter than the balls in another chamber. 10. A composition according to claim 9 wherein: 4 48 4 9 48 9 9 9 4 9999 49 that is obtainable using beads of sizes between 0.4 mm and 1.25 mm in each chamber. Composition according to any one of claims 1 to 10, characterized in that it comprises a soluble carrier suitable as an additive for spray drying. The composition of claim 10, wherein the soluble carrier is mannitol. Composition according to any one of claims 1 to 12, characterized in that it contains a surfactant for keeping the particles in suspension during grinding and repeated suspension. 14. The composition of claim 13 wherein the surfactant is sodium lauryl sulfate. A composition according to any one of claims 1 to 14 comprising an anti-agglomeration agent effective after administration of the pharmaceutical composition to a patient. 16. The composition of claim 15 wherein the anti-agglomerating agent is hydroxypropyl methylcellulose. 17. A method of preparing a composition comprising a poorly water-soluble drug in particulate form comprising grinding the drug in the form of an aqueous dispersion in a multi-chamber ball grinder with circulation of material between chambers, wherein the aqueous dispersion comprises a soluble carrier suitable as a spray drying additive; a suspension and re-suspension surfactant; and an anti-agglomeration agent effective after administration of the pharmaceutical composition to a patient, and further comprising a method of spray drying the aqueous dispersion obtained after grinding. The method of claim 17, wherein the medicament is a compound of Formula I or Formula II. The method of claim 18, wherein the ground aqueous dispersion comprises about 10 to 30% (w / w) of a compound of Formula I or II, about 4 to 15% (w / w) of a soluble carrier, about 0 1 to 0.4% (w / w) of a surfactant and about 1% to 2% (w / w) of an anti-agglomerating agent. Method of treatment and / or prophylaxis of anxiety, mania, depression, panic disorder and / or aggression, diseases associated with subarachnoid hemorrhage or nerve shock, conditions associated with withdrawal symptoms depending on cocaine, nicotine, alcohol and benzodiazepines, treatable and / or or capable of preventing anticonvulsants such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia, obsessive-compulsive disease (OCD), AIDS-related neurological deficits , sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (such as Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, toothache, tumor pain, inadequate neuronal activity as a result of neurodysest esia in diseases such as diabetes mellitus, multiple sclerosis (MS) and motor neuron diseases, ataxia, muscle rigidity (spasticity), temporomandibular arthritis dysfunction and / or amyotrophic lateral sclerosis (ALS), characterized in that individuals in need of such treatment are administered an effective or prophylactic amount of the composition of any one of claims 1 to 10 16. Use of a composition according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment and / or prophylaxis of anxiety, mania, depression, panic disorder and / or aggression, diseases associated with subarachnoid haemorrhage or nerve shock, conditions associated with withdrawal symptoms depending on cocaine, nicotine, alcohol and benzodiazepines, diseases treatable and / or capable of preventing anticonvulsants such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia, obsessive -compulsive disease (OCD), AIDS-related neurological deficits, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (such as Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain , toothache, tumor bo asthma, inadequate neuronal activities due to neurodysesthesia in diseases such as diabetes mellitus, multiple sclerosis (MS) and motor neuron diseases, ataxia, muscle rigidity (spasticity), temporomandibular articulation dysfunction and / or amyotrophic lateral sclerosis (ALS). Method of treatment and / or prophylaxis of anxiety, mania, depression, panic disorder and / or aggression, diseases associated with subarachnoid hemorrhage or nerve shock, conditions associated with withdrawal symptoms depending on cocaine, nicotine, alcohol and benzodiazepines, diseases treatable and / or or capable of preventing anticonvulsants such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative 9 9 9 · 99 • 9 9 9 9 999999 99 99 diseases such as Huntington's chorea, schizophrenia, obsessive-compulsive disease (OCD), AIDS-related neurological deficits, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (eg Giles de la Tourette syndrome), traumatic injury brain, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, toothache, cancer pain, inadequate neuronal activity due to neurodysesthesia in diseases such as diabetes mellitus, multiple sclerosis (MS) and motor neuron diseases, ataxia, muscle rigidity (spasticity) , temporomandibular articular dysfunction and / or amyotrophic lateral sclerosis (ALS), characterized in that an individual in need of such treatment is administered an effective amount of a compound of Formula I or II, or a pharmaceutically acceptable salt or solvate thereof, and optionally, a pharmaceutically acceptable carrier.