Injectable formulations of multicyclic antidepressants

Abstract

The invention relates to a composition comprising a piperazine-benzazepine, a buffer and a surfactant, and uses of such compositions such as treating, preventing, and / or suppressing symptoms of schizophrenia, schizoaffective disorders, and / or Parkinson's disease. The compositions have improved parameters such as a lower variance in pH, improved stability during storage, and lower solubility of piperazine-benzazepines, resulting in piperazine-benzazepine particle formation with improved particle size and particle size distribution. The compositions are useful as therapeutic agent, for instance through parenteral administration to a subject.

Description

[0001] Injectable formulations of multicyclic antidepressants

[0002] Field of the invention

[0003] The invention relates to a composition comprising a piperazine-benzazepine, a buffer and a surfactant, and uses of such compositions such as treating, preventing, and / or suppressing symptoms of schizophrenia, schizoaffective disorders, and / or Parkinson's disease. The compositions have improved parameters such as a lower variance in pH, improved stability during storage, and lower solubility of piperazine-benzazepines, resulting in piperazine-benzazepine particle formation with improved particle size and particle size distribution. The compositions are useful as therapeutic agent, for instance through parenteral administration to a subject.

[0004] Background art

[0005] Piperazine-benzazepines such as clozapine (CAS number: 5786-21-0, 8-chloro-11-(4-methyl- 1-piperazinyl-5 / 7-dibenzo[b,e][1 ,4])diazepine) is a well-known compound having anti-psychotic activity. Clozapine is the first second-generation antipsychotic with primary application in people with schizophrenia and schizoaffective disorder who have had an inadequate response to other antipsychotics. It is also used for the treatment of psychosis in Parkinson's disease. It works by balancing the levels of dopamine and serotonin in your brain, substances that help regulate mood. Details about this compound are disclosed in monograph 2448 of the 13thedition of the Merck Index, the disclosure of which is hereby incorporated by way of reference.

[0006] Clozapine is traditionally applied as oral dosage form, for example as a tablet. For patients who have difficulty swallowing or who feign ingestion, liquid formulations of clozapine for oral administration have been developed, see the formulation disclosed in EP1646393. However, since the oral bioavailability is only 60-70%, there is a need for formulations suitable for other administration routes.

[0007] A known problem that is faced in the development of liquid formulations of clozapine is that clozapine is not well-soluble in water. An option for preparing a liquid formulation is to form it into an aqueous suspension. However, when clozapine is simply added directly to water, the compound settles rapidly to form a dense cake at the base of the aqueous mixture. The caking cannot easily be redistributed and as such would compromise the accuracy of drug dose delivered to a patient. To overcome this, a standard formulation technique would be to use a suitable surfactant to promote flocculation. Flocculation is a process where suspended particles agglomerate, forming larger particles that settle loosely and can be readily re-dispersed with gentle shaking.

[0008] While clozapine can generally be regarded as a stable molecule, when formed into an aqueous suspension with a surfactant and other formulating agents, the stability of the formulation is poor. The formulation can be susceptible to hydrolysis, particularly on extended storage. As a result, the accuracy of the drug dose delivered to the patient could be compromised.

[0009] In addition to formulation stability, the maintenance of an appropriate particle size distribution is also critical when parenteral administration is intended. For such administration USP chapter 1151 suggests that particles should adhere to certain sizes and size distributions. EP1646393 is silent on particle size and size distribution. To ensure physical stability of the formulation, the suspension should be as monodisperse as possible. There would be a clear advantage to be able to provide a physicochemical stable suspension formulation of clozapine for parenteral administration which would retain its physico-chemical stability over a prolonged storage period. Such a product characteristic would be important to the production and stability of a commercial liquid formulation.

[0010] Summary of the invention

[0011] The inventors have surprisingly found new compositions comprising piperazine-benzazepines, the compositions comprising piperazine-benzazepine particles that are small in size and have a limited particle size distribution, and also have a stable, physiological pH and osmolarity. The piperazine- benzazepine compositions have improved characteristics suitable for parenteral administration. The compositions are particularly suitable for being milled.

[0012] The invention provides a composition comprising a piperazine-benzazepine, a buffer, and a surfactant, wherein the buffer is a phosphate buffer; and the surfactant is a non-ionic block copolymer surfactant. Preferably the buffer has a pH of 6.5-8.5, preferably of 7-8. Preferably the buffer is a 1-30 mM phosphate buffer, preferably 2-25 mM, more preferably 3-20 mM, most preferably 4-15 mM. Preferably the composition comprises at least 2.5 wt.-% surfactant. Preferably the block copolymer comprises a hydrophobic block flanked by two hydrophilic blocks. The composition preferably comprises 1-15 wt.-% piperazine-benzazepine, preferably 2.5-10 wt.-%, such as 5 wt.-%, wherein the piperazine-benzazepine is preferably clozapine.

[0013] In some embodiments the composition further comprises a tonicifier, such as a carbohydrate, a sugar alcohol, or a hydrophylic polymer, preferably the composition comprises 1 -10 wt.-% tonicifier, more preferably 2.5-7.5 wt.-%, most preferably around 5 wt.-%. In some embodiments the composition further comprises a suspending agent such as polyvinylpyrrolidone, preferably between 0.1 -5 wt.-% suspending agent, more preferably 0.2-4 wt.-%, still more preferably 0.3-3 wt.-%, still more preferably 0.4-2 wt.-%, most preferably around 0.5 wt.-%, wherein the pH of the composition is preferably about 7-8 such as 7.5. Preferably the osmolality of the composition is below 600 mOsm / kg, preferably between 250-500 mOsm / kg, more preferably between 350-450 mOsm / kg.

[0014] The composition is generally a nanoparticle suspension. Preferably 90% of the particles have a particle size smaller than 10 pm, preferably between 0.1-5 pm, such as about 2.5 pm; or wherein the particles have a particle size distribution with a span less than 5, preferably between 1 -4, more preferably between 1.5-3.5, most preferably between 2-3. Preferably the composition is stable during storage for at least 2 weeks, preferably for at least about 4 weeks, wherein storage conditions are preferably at 2-8°C or at 25°C with a relative humidity of about 60%.

[0015] In some embodiments the composition has a pH of about 7.5-8, and / or the buffer is a 4-6 mM phosphate buffer, and / or the composition comprises about 2.5-5.5 wt.-% surfactant, and / or the composition comprises about 4-6 wt.-% clozapine, and / or the composition comprises about 4-6 wt.-% sugar alcohol, and / / or the composition comprises about 0.4-0.6 wt.-% polyvinylpyrrolidone. In some embodiments the buffer is a 5 mM phosphate buffer and the composition comprises about 5 wt.-% clozapine and about 5 wt.-% mannitol, wherein the composition further comprises: i) about 3 wt.-% poloxamer 338, wherein the pH of the composition is 8; or ii) about 5 wt.-% poloxamer 338, wherein the pH of the composition is 8; or iii) about 3 wt.-% poloxamer 338 and about 0.2 wt.-% poloxamer 188, wherein the pH of the composition is 8; or iv) about 3 wt.-% poloxamer 338 and about 0.5 wt.-% polyvinylpyrrolidone, wherein the pH of the composition is 8; or v) about 3 wt.-% poloxamer 338, wherein the pH of the composition is 7.5; or vi) about 3 wt.-% poloxamer 338 and about 0.5 wt.-% polyvinylpyrrolidone, wherein the pH of the composition is 7.5.

[0016] Also provided is a method for treating, preventing, and / or suppressing symptoms of schizophrenia, schizoaffective disorders, and / or Parkinson's disease, wherein the method comprising the step of administering to a subject a composition as described above. Also provided is the composition as described above, for use in such a method.

[0017] Description of embodiments

[0018] The inventors have surprisingly found new compositions comprising piperazine-benzazepines, the compositions comprising piperazine-benzazepine particles that are small in size and have a limited particle size distribution, and also have a stable, physiological pH and osmolarity. The piperazine- benzazepine compositions have improved characteristics suitable for parenteral administration. The compositions are particularly suitable for being milled.

[0019] Accordingly the invention provides a composition comprising a piperazine-benzazepine, a buffer, and a surfactant, wherein the buffer is a phosphate buffer; and the surfactant is a non-ionic block copolymer surfactant. Such a composition is referred to herein as a composition according to the invention.

[0020] Piperazine-benzazepines are known in the art. Preferred ones are piperazine-dibenzazepines. More preferred piperazine-benzazepines are of general formula (I) or a pharmaceutically acceptable salt thereof or optionally a metabolite thereof, wherein

[0021] - X is -O-, -S-, or -N(H)-,

[0022] - R is -H, -CH3, or -(CH2)2-O-(CH2)2-OH,

[0023] L’ and L” are each independently chosen from the group consisting of -H, -CH3, and halogen, wherein halogen is preferably chlorine,

[0024] Q’ and Q” together form -CH=CH- or -S-, preferably wherein when Q’ and Q” together form -S-, L” is -CH3. An important feature of piperazine-benzazepines of general formula (I) is that two heterocycles are fused to the azepine moiety. When Q’ and Q” together form -S-, this could be seen as one of Q’ and Q” being sulphur, and the other of Q’ and Q” being absent. In such a case, the second heterocycle fused to the azepine moiety is an aromatic heterocycle (thiophenyl), due to lone pairs of the sulphur atom. When Q’ and Q” together form -CH=CH-, this could be seen as both Q’ and Q” being -CH=. In such a case, the second heterocycle fused to the azepine moiety is also an aromatic cycle (phenyl).

[0025] In preferred embodiments of the invention, the composition according to the invention comprises a piperazine-benzazepine of general formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0026] - X is -O-, -S-, or -N(H)-,

[0027] - R is -H, -CH3, or -(CH2)2-O-(CH2)2-OH,

[0028] L’ and L” are each independently chosen from the group consisting of -H, -CH3, and chlorine,

[0029] Q’ and Q” together form -CH=CH- or -S-, preferably, wherein when Q’ and Q” together form -S-, L” is -CH3.

[0030] When X is -O-, it is preferred that Q’ and Q” together form -CH=CH-. When X is -O-, it is preferred that L’ is -H. When X is -O-, it is preferred that L” is -Cl. When X is -O-, it is preferred that R is -CH3or -H. Most preferably, when X is -O-, R is -CH3or -H, L’ is -H, L” is -Cl, and Q’ and Q” together form -CH=CH-.

[0031] When X is -S-, it is preferred that Q’ and Q” together form -CH=CH-. When X is -S-, it is preferred that L’ is -H. When X is -S-, it is preferred that L” is -Cl or -H. When X is -S-, it is preferred that R is -CH3or -(CH2)2-O-(CH2)2-OH. More preferably, when X is -S-, R is -CH3or -H or -(CH2)2-O- (CH2)2-OH, L’ is -H, L” is -Cl or -H, and Q’ and Q” together form -CH=CH-. Most preferably, when X is -S-, R is -CH3or -(CH2)2-O-(CH2)2-OH, L’ is -H, L” is -Cl or -H, and Q’ and Q” together form -CH=CH-.

[0032] When X is -N(H)-, it is preferred that L” is -CH3or -H, and it is more preferred that L” is -CH3when Q’ and Q” together form -S-, and that L” is -H when Q’ and Q” together form -CH=CH-. When X is -N(H)-, it is preferred that L’ is -H or -Cl. When X is -N(H)-, it is preferred that R is -H or -CH3. Most preferably, when X is -N(H)-, R is -H or -CH3, L’ is -Cl or -H, and L” is -CH3or -H.

[0033] In preferred compositions according to the invention, the composition comprises at least one piperazine-benzazepine of general formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0034] R is -CH3, L’ is -Cl, L” is -H, X is -N(H)-, and Q’ and Q” together form -CH=CH-, or

[0035] R is -H, L’ is -Cl, L” is -H, X is -N(H)-, and Q’ and Q” together form -CH=CH-, or

[0036] R is -CH3, L’ is -H, L” is -CH3, X is -N(H)-, and Q’ and Q” together form -S-, or

[0037] R is -H, L’ is -H, L” is -CH3, X is -N(H)-, and Q’ and Q” together form -S-, or

[0038] R is -CH3, L’ is -H, L” is -Cl, X is -O-, and Q’ and Q” together form -CH=CH-, or

[0039] R is -H, L’ is -H, L” is -Cl, X is -O-, and Q’ and Q” together form -CH=CH-, or

[0040] R is -CH3, L’ is -H, L” is -Cl, X is -S-, and Q’ and Q” together form -CH=CH-, or

[0041] R is -(CH2)2-O-(CH2)2-OH, L’ is -H, L” is -H, X is -S-, and Q’ and Q” together form -CH=CH-, or R is -H, L’ is -H, L” is -Cl, X is -S-, and Q’ and Q” together form -CH=CH-. Accordingly, the invention provides a composition according to the invention, wherein the piperazine-benzazepine of general formula (I) is selected from clozapine, norclozapine, olanzapine, norolanzapine, loxapine, amoxapine, clotiapine, quetiapine, and norquetiapine, or a pharmaceutically acceptable salt thereof, preferably clozapine or a pharmaceutically acceptable salt thereof. In preferred embodiments the invention provides a composition comprising clozapine, a buffer, and a surfactant, wherein the buffer is a phosphate buffer; and the surfactant is a non-ionic block copolymer surfactant. clozapine norclozapine olanzapine norolanzapine norquetiapine

[0042] Metabolites of piperazine-benzazepines of general formula (I) are also encompassed by the invention. Such metabolites can also be encompassed by general formula (I). For example, norclozapine (also known as A / -desmethylclozapine, NDMC, desmethylclozapine, and 8-chloro-11- piperazin-1 -yl-5 / 7-dibenzo[b,e][1 ,4]diazepine) is a metabolite of clozapine (also known as clozaril and 8-Chloro-11-(4-methylpiperazin-1-yl)-5 / 7-dibenzo[b,e][1 ,4]diazepine). Norolanzapine (also known as 2- Methyl-4-piperazin-1-yl-10 / 7-thieno[2,3-b][1 ,5]benzodiazepine) is a metabolite of olanzapine (also known as Zyprexa and 2-Methyl-4-(4-methyl-1-piperazinyl)-10 / 7-thieno[2,3-b][1 ,5]benzodiazepine). Amoxapine (also known as Asendin, Asendis, Defanyl, Demolox, and 2-chloro-11 -(piperazin-1- yl)dibenzo[b,f|[1 ,4]oxazepine) is a metabolite of loxapine (also known as adasuve, loxitane, loxapac, xylac, and 2-Chloro-1 1-(4-metyl-1-piperazinyl)dibenz[b, / ][1 ,4]oxazepine). Norquetiapine (also known as 8-chloro-6-piperazin-1-yl-benzo[b][1 ,4]benzothiazepine) is a metabolite of quetiapine (also known as Seroquel, Temprolide, and 2-(2-(4-Dibenzo[b,f|[1 ,4]thiazepine-11-yl-1-piperazinyl)ethoxy)ethanol) and of clotiapine (also known as Etumina, Etumine, Entumin, Etomine, Entumine, and 8-chloro-6-(4- methylpiperazin-1-yl)benzo[b][1 ,4]benzothiazepine.) Other metabolites are known in the art.

[0043] Compositions preferably comprise at least 0.5 wt.-% piperazine-benzazepine, more preferably at least 1 wt.-%. Compositions preferably comprise at most 20 wt.-% piperazine-benzazepine, more preferably at most 15 wt.-%. In preferred embodiments the invention provides the composition according to the invention, wherein the composition comprises 1 -15 wt.-% piperazine-benzazepine, preferably 2.5-10 wt.-%, such as 5 wt.-%, wherein the piperazine-benzazepine is preferably clozapine. In some embodiments the composition comprises 1 .5-14.5 wt.-% piperazine-benzazepine, in further embodiments the composition comprises 2-14, 2.5-13.5, 3-13, 3.5-12.5, 3.6-12, 3.7-11 .5, 3.8-11 , 3.9-

[0044] 10.5, 4-10, 4.1-9.5, 4.2-9, 4.3-8.5, 4.4-8, 4.5-7.5, 4.6-7.4, 4.7-7.3, 4.8-7.2, 4.9-7.1 , 5-7, 5.1-6.9, 5.2-6.8,

[0045] 5.3-6.7, 5.4-6.6, 5.5-6.5, 5.6-6.4, 5.7-6.3, 5.8-6.2, 5.9-6.1 , or 5.9-6 wt.-% piperazine-benzazepine. Particularly preferred ranges are 3-8 wt.-%, and 3.5-7.5 wt.-%, more preferably 4-6.5 or 4-6 wt.-%.

[0046] Compositions according to the invention comprise a buffer, which is a phosphate buffer. The buffer generally functions as the vehicle and is therefore preferably present in an amount to fill out the intended volume. For example, for a composition of pH 8 wherein the buffer is a 5 mM phosphate buffer and the composition comprises 5 wt.-% clozapine, 5 wt.-% mannitol, and 3 wt.-% poloxamer 338, the composition preferably comprises 87 wt.-% of the buffer. It was found that a phosphate buffer was particularly useful as a suitable anti-solvent for the piperazine-benzazepine, to ensure suitable particle formation and stability.

[0047] A skilled person is aware of how to prepare a suitable phosphate buffer, particularly when a pH and a molarity are provided. Buffers for use in compositions according to the invention preferably have a pH of 6-9, more preferably the buffer has a pH of 6.5-8.5, most preferably of 7-8. In some embodiments the buffer has a pH of 6.6-8.4, 6.7-8.3, 6.8-8.2, 6.9-8.1 , 7-8, 7.1-7.9, 7.2-7.8, 7.3-7.7, or

[0048] 7.4-7.6. As is commonly known the pH of a buffer can be suitably set using for instance HCI or NaOH solutions. Generally, the pH of the buffer determines the pH of the composition.

[0049] The molarity of the phosphate buffer can be at least 0.5 mM, although at least 1 mM is preferred. It can be at most 60 mM, although at most 50 mM is preferred. Preferably the buffer is a 1-30 mM phosphate buffer, preferably 2-25 mM, more preferably 3-20 mM, most preferably 4-15 mM. In some embodiments the buffer is a 2.5-19, 2.6-18, 2.7-17, 2.8-16, 2.9-15, 3-14.5, 3.1-14, 3.2-13.5, 3.3-13, 3.4-

[0050] 12.5, 3.5-12, 3.6-11.5, 3.7-11 , 3.8-10.5, 3.9-10, 4-9.8, 4.1-9.6, 4.2-9.4, 4.3-9.2, 4.4-9, 4.5-8.8, 4.6-8.6, 4.7-8.4, 4.8-8.2, 4.9-8, 5-7.8, 5.1 -7.6, 5.2-7.4, 5.3-7.2, 5.4-7, 5.5-6.9, 5.6-6.8, 5.7-6.7, 5.8-6.6, 5.9-6.5, 6-6.4, 6.1-6.3, or 6.2-6.3 mM phosphate buffer.

[0051] A preferred phosphate buffer comprises sodium phosphate. A preferred phosphate buffer comprises water and appropriate salts. A preferred phosphate buffer can be provided by mixing suitable amounts of phosphate salts. Suitable phosphate salts are disodium hydrogen phosphate, for instance its dihydrate, and sodium dihydrogen phosphate, for instance its dihydrate.

[0052] Compositions according to the invention comprise a surfactant, which is a non-ionic block copolymer surfactant. This class of compounds is well-known, and a skilled person can tell whether or not compounds are in this class. Block copolymers comprise two or more blocks of distinct polymers. In a block copolymer surfactant, one block is generally water soluble (for example a poly(ethylene glycol), or PEG, block), and one other block is generally hydrophobic (for example a polystyrene block). Examples of non-ionic block copolymer surfactants are polystyrene-PEG, polycaprolactone-PEG, and polypropylene glycol)-PEG, the latter of which is preferred. Non-ionic generally refers to polymers that do not comprise ionic monomers. Examples of non-ionic polymers are PEG and polypropylene glycol).

[0053] In preferred embodiments the block copolymer comprises a hydrophobic block flanked by two hydrophilic blocks. Examples of such block copolymers are PEG-polystyrene-PEG, or PEG- polypropylene glycol)-PEG. This latter class of PEG-PPG-PEG is known as poloxamers, which are highly preferred non-ionic block copolymer surfactant for compositions according to the invention. Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polypropylene glycol) (also known as polyoxypropylene or as polypropylene oxide)) flanked by two hydrophilic chains of PEG (also known as polyoxyethylene or polypthylene oxide)). Poloxamers are also known by the trade names Pluronic, Kolliphor, and Synperonic. The generic CAS No. 9003-11-6 applies to all poloxamers.

[0054] Poloxamers can have varying chain lengths. Preferably the poloxamer is symmetric, in the sense that the flanking PEG blocks are of equal length. It should be understood that when discussing polymers, known and accepted degrees of polydispersity apply. Preferred poloxamers are pharmaceutical grade poloxamers. The table below gives an overview of known and commercially available poloxamers, including numbers that are used as names. For instance, poloxamer 101 is PEG2-PPG16-PEG2, and is also known as Pluronic L-31. Poloxamer 188 is PEG75-PPG30-PEG75 and is also known as Pluronic F-68. Poloxamer 338 is PEG128-PPG54-PEG128 and is also known as Pluronic F-108.

[0055]

[0056] The compositions can comprise any suitable amount of surfactant, preferably at least 1 .5 wt.- %, more preferably at least 2 wt.-%, even more preferably at least 2.5 wt.-%. The compositions preferably comprise at most 12 wt.-%, more preferably at most 10 wt.-%, still more preferably at most 6 wt.-% of the surfactant. In preferred embodiments the composition comprises 1.6-5.4, 1.7- 5.3, 1.8- 5.2, 1.9-5.1 , 2-5, 2.1-4.9, 2.2-4.8, 2.3-4.7, 2.4-4.6, 2.5-4.5, 2.6-4.4, 2.7-4.3, 2.8-4.2, 2.9-4.1 , 3-4, 3.1- 3.9, 3.2-3.8, 3.3-3.7, 3.4-3.6, or 3.5-3.6 wt.-% surfactant, more preferably wt.-% poloxamer. Particularly good results were obtained with compositions comprising about 3 wt.-% poloxamer, about 3.2 wt.-% poloxamer, and about 5 wt.-% poloxamer - accordingly compositions comprising about 2.9-5.1 wt.-% poloxamer are greatly preferred. In some preferred embodiments the composition comprises at least 4, preferably at least 4.5, more preferably at least 4.8 such as about 5 wt.-% surfactant.

[0057] Good results were obtained with Poloxamer 188 (PEG75-PPG30-PEG75) and with poloxamer 338 (PEG 128-PPG54-PEG128). Therefore preferred poloxamers comprises PEG blocks with a length of about 65 to about 140, and preferred poloxamers comprises PPG blocks with a length of about 25 to about 60, more preferably both such PEG blocks and such PPG blocks. More preferred poloxamers comprises PEG blocks with a length of about 70 to about 130, and more preferred poloxamers comprises PPG blocks with a length of about 28 to about 57, more preferably both such PEG blocks and such PPG blocks. Preferred poloxamers have PEG blocks that each comprise about 2.1 -2.7 times the amount of monomers as compared to the PPG block, preferably about 2.2-2.6 times, more preferably about 2.3-2.6 times, most preferably about 2.35-2.55 times.

[0058] Examples of preferred poloxamers are poloxamer 188, poloxamer 238, poloxamer 288, and poloxamer 338, more preferred are poloxamer 188 and poloxamer 338, most preferred is poloxamer 338. In some embodiments only a single type of surfactant is present. In some embodiments only a single type of poloxamer is present. In some embodiments two or more types of surfactant are present. In some embodiments two or more types of poloxamer are present. A preferred combination of surfactants is poloxamer 188 and poloxamer 338.

[0059] Preferred compositions further comprise a tonicifier, such as a carbohydrate, a sugar alcohol, or a hydrophylic polymer, preferably the composition comprises 1 -10 wt.-% tonicifier, more preferably 2.5-7.5 wt.-%, most preferably around 5 wt.-%. Preferably, the formulation of the invention is substantially isotonic to human blood, or is hypertonic. More preferably it is hypertonic. Tonicity is a measure for the effective osmotic pressure that a liquid formulation can exert, and depends primarily on the number of dissolved particles in solution. Osmotic pressure is an important factor affecting biological cells. Hypertonicity is the presence of a solution that causes cells to shrink. Hypotonicity is the presence of a solution that causes cells to swell. Isotonicity is the presence of a solution that produces no change in cell volume. When a biological cell is in a hypotonic environment, the cell interior accumulates water, water flows across the cell membrane into the cell, causing it to expand. For mammalian cells this can lead to cytolysis, and tonicity is therefore important when fragile cells are to be exposed to a composition. Tonicity agents can therefore be added to preparations such as injectable preparations to prevent osmotic shock at the site of injection upon administration, and thereby reduce local irritation or even damage to tissues or cells.

[0060] Preferably, the composition has a tonicity that is suitable for injection. Preferably the osmolality of the composition is below 600 mOsm / kg, preferably between 250-500 mOsm / kg, more preferably between 350-450 mOsm / kg. The osmolality can be 260-490, 270-480, 280-470, 290-460, 300-450, 310-440, 320-430, 330-420, 340-410, 350-400, 360-390, 370-380, or 375-380 mOsm / kg. An osmolality below 600 mOsm / kg is attractive for balancing stability of the piperazine-benzazepine with good injection volumes, and lower values can increase patient comfort. Values above 250 mOsm / kg are attractive for avoiding hypotonicity, which can cause tissue damage. In other embodiments the composition is substantially isotonic to human blood, which has a tonicity or osmotic concentration of about 290 mOsm / kg. In particular, the composition may have an osmolality, also referred to as tonicity or osmotic concentration, of from 250 to 330 mOsm / kg, such as 260 to 310 mOsm / kg. In some preferred embodiments, the composition has an osmolality of from 260 to 320 mOsm / kg, more preferably from 270 to 315 mOsm / kg, most preferably from 274 to 310 mOsm / kg. For example, the composition can have an osmolality of 290 mOsm / kg. Preferably the osmolality of the composition is determined at room temperature, such as between 18 to 24 °C, most preferably between 21 to 23 °C, such as at 22 °C.

[0061] Typical tonicifiers, also known as tonicity agents, are excipients used for tonicity adjustment, and are known in the art. Tonicity agents can include carbohydrates such as dextrose, sugar alcohols such as mannitol, amino acids such as glycerin, hydrophilic polymers such as PEG, and metal salts. Preferred metal salts are pharmaceutically acceptable metal salts such as NaCI, KCI, CaCh, MgCh, or combinations thereof. Preferred carbohydrates are hexoses such as aldohexoses or ketohexoses. Because good results were obtained with mannitol, all of arabitol, erythritol, mannitol, sorbitol, and xylitol are preferred sugar alcohols, which are preferred tonicifiers, of which mannitol is most preferred. Preferably the composition comprises 1 -10 wt.-% tonicifier, more preferably 2.5-7.5 wt.-%, most preferably around 5 wt.-%. In some embodiments the composition comprises 1.5-9, 2-8, 3-7, 3.5-6.5, preferably 4-6 wt.-% tonicifier, more preferably 4-6 wt.-% sugar alcohol, even more preferably 4-6 wt.- % arabitol, erythritol, mannitol, sorbitol, or xylitol, most preferably about 5 wt.-% mannitol.

[0062] Preferred compositions can further comprise a suspending agent such as polyvinylpyrrolidone, preferably between 0.1-5 wt.-% suspending agent, more preferably 0.2-4 wt.-%, still more preferably 0.3-3 wt.-%, still more preferably 0.4-2 wt.-%, most preferably around 0.5 wt.-%, wherein the pH of the composition is preferably about 7-8 such as 7.5. The composition can comprise between 0.25-4.5, 0.35- 3.5, 0.45-2.5 wt.-% suspending agent, more preferably 0.35-2.1 wt.-%. In some embodiments about 0.5 wt.-% or about 2 wt.-% are comprised. Most preferably 0.4-0.6 wt.-% are comprised.

[0063] Suspending agents are known in the art. Preferred suspending agents are polymers, more preferably water-soluble polymers. Suspending agents generally increase the viscosity of the composition and help reduce the settling, sedimentation, and / or aggregation of suspended particles. Suspending agents can be water-soluble polymers and inorganic salts such as bentonite, aluminium hydroxide, or aluminium magnesium silicate. Water-soluble polymers are preferred, and suitable examples are methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, alginate, polyvinylpyrrolidone (PVP), cellulose, and gums, of which PVP is most preferred.

[0064] Polyvinylpyrrolidone (PVP) is also commonly called polyvidone or povidone or kollidon, and is a water-soluble polymer of the monomer N-vinylpyrrolidone. PVP is widely available in a range of molecular weights and related viscosities, and can be selected according to the desired application properties. A preferred PVP has a molecular weight of about 25-60 kDa, such as about 30-50 kDa, preferably about 35-45 kDa, most preferably about 40 kDa, which is commercially available as PVP K30, or kollidon 30. For compositions comprising a suspending agent, particularly comprising PVP, it is preferred that the pH is below 8, preferably that the pH is in the range of 7-7.8, more preferably in the range of 7.3-7.7, such as about 7.5. In some preferred embodiments, no suspending agent is present - it was found that such compositions could achieve good particle size distribution with reduced milling time. Preferred compositions do not comprise an ionic surfactant, more preferably do not comprise dioctyl sodium sulfosuccinate.

[0065] In preferred embodiments the composition is provided, wherein

[0066] 1) the composition has a pH of about 7.5-8, and / or

[0067] 2) the buffer is a 4-6 mM phosphate buffer, and / or

[0068] 3) the composition comprises about 2.5-5.5 wt.-% surfactant, and / or

[0069] 4) the composition comprises about 4-6 wt.-% clozapine, and / or

[0070] 5) the composition comprises about 4-6 wt.-% sugar alcohol, and / / or

[0071] 6) the composition comprises about 0.4-0.6 wt.-% polyvinylpyrrolidone.

[0072] In some embodiments, 1 and 2 apply. In some embodiments, 1 and 3 apply. In some embodiments, 1 and 4 apply. In some embodiments, 1 and 5 apply. In some embodiments, 1 and 6 apply. In some embodiments, 2 and 3 apply. In some embodiments, 2 and 4 apply. In some embodiments, 2 and 5 apply. In some embodiments, 2 and 6 apply. In some embodiments, 3 and 4 apply. In some embodiments, 3 and 5 apply. In some embodiments, 3 and 6 apply. In some embodiments, 4 and 5 apply. In some embodiments, 4 and 6 apply. In some embodiments, 5 and 6 apply. In some embodiments, 1 , 2, and 3 apply. In some embodiments, 1 , 2, and 4 apply. In some embodiments, 1 , 2, and 5 apply. In some embodiments, 1 , 2, and 6 apply. In some embodiments, 1 , 3, and 4 apply. In some embodiments, 1 , 3, and 5 apply. In some embodiments, 1 , 3, and 6 apply. In some embodiments, 1 , 4, and 5 apply. In some embodiments, 1 , 4, and 6 apply. In some embodiments, 1 , 5, and 6 apply. In some embodiments, 2, 3, and 4 apply. In some embodiments, 2, 3, and 5 apply. In some embodiments, 2, 3, and 6 apply. In some embodiments, 2, 4, and 5 apply. In some embodiments, 2, 4, and 6 apply. In some embodiments, 2, 5, and 6 apply. In some embodiments, 3, 4, and 5 apply. In some embodiments, 3, 4, and 6 apply. In some embodiments, 3, 5, and 6 apply. In some embodiments, 4, 5, and 6 apply. In some embodiments, 1 , 2, 3, 4, and 5 apply. In some embodiments, 1 , 2, 3, 4, and 6 apply. In some embodiments, 1 , 2, 3, 5, and 6 apply. In some embodiments, 1 , 2, 4, 5, and 6 apply. In some embodiments, 1 , 3, 4, 5, and 6 apply. In some embodiments, 2, 3, 4, 5, and 6 apply. In some embodiments all of 1 , 2, 3, 4, 5, and 6 apply.

[0073] Particularly preferred embodiments are those wherein the buffer is a 5 mM phosphate buffer and the composition comprises about 5 wt.-% clozapine and about 5 wt.-% mannitol, wherein the composition further comprises: i) about 3 wt.-% poloxamer 338, wherein the pH of the composition is 8; or ii) about 5 wt.-% poloxamer 338, wherein the pH of the composition is 8; or iii) about 3 wt.-% poloxamer 338 and about 0.2 wt.-% poloxamer 188, wherein the pH of the composition is 8; or iv) about 3 wt.-% poloxamer 338 and about 0.5 wt.-% polyvinylpyrrolidone, wherein the pH of the composition is 8; or v) about 3 wt.-% poloxamer 338, wherein the pH of the composition is 7.5; or vi) about 3 wt.-% poloxamer 338 and about 0.5 wt.-% polyvinylpyrrolidone, wherein the pH of the composition is 7.5.

[0074] Because the phosphate buffer is a good anti-solvent for the piperazine-benzazepine, the composition is a suspension. Generally, within the parameters of the invention, the composition is a nanoparticle suspension. In the context of the invention, nanoparticles are particles that are generally smaller than 50pm, preferably smaller than 20 pm, more preferably smaller than 15 pm. In preferred embodiments, 90% of the particles have a particle size smaller than 10 pm, preferably between 0.1-5 pm, such as about 2.5 pm. Preferably 90% of the particles have a particle size smaller than 9, 8, 7, 6.5, 6.2, 6, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1 , or 5 pm, more preferably 90% of the particles have a particle size smaller than 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1 , 4, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1 , or 3 pm, most preferably 90% of the particles have a particle size smaller than 2.9, 2.8, 2.7, 2.6, or 2.5 pm. Nanoparticle size can be determined using any technique known in the art, such as microscopy or preferably laser diffraction. Span is a parameter that indicates the width of particle size distribution. A direct correlation exists between the width of particle size distribution and the span value, which means that the smaller the span value is, the narrower the particle size distribution is. The parameter Dv90 signifies the point in the size distribution, up to and including which 90% of the total volume of particles in the sample is contained. For example, if the Dv90 is 2.5 pm, this means that 90% of the sample has a size of 2.5 pm or smaller. The definition for Dv50 is the size point below which 50% of the particles are contained, and Dv10 is the size below which 10% of the particles is contained. This description has long been used in size distribution measurements by laser diffraction, and a skilled person can determine and interpret Dv10, Dv90, and Dv50 values. The span of a volume-based size distribution is defined as Span = (Dv90 - Dv10) / Dv50 and thus it gives an indication of how far the 10 percent and 90 percent points are apart, normalized with the midpoint.

[0075] Preferably the particles have a particle size distribution with a span less than 5, more preferably between 1 -4, even more preferably between 1.5-3.5, most preferably between 2-3. In some embodiments span is between 1.6-3.4, 1.7-3.3, 1.8-3.2, 1.9-3.1 , 2.1-2.9, 2.2-2.8, 2.3-2.7, 2.4-2.6, or about 2.5. Preferably the particle size distribution is determined by laser diffraction.

[0076] The compositions are particularly stable and can be milled advantageously to promote their uniformity. Compositions are provided that are stable during storage for at least 2 weeks, preferably for at least about 4 weeks, wherein storage conditions are preferably at 2-8°C or at 25°C with a relative humidity of about 60%. The compositions are preferably stable for at least 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, or 40 days, more preferably for at least 28 days. In preferred embodiments stability means that the substance of general formula (I) does not degrade to a relevant degree, and that degradation products of substances of general formula (I) do not appear over time. In this context, a substance of general formula (I) can be said to be stable if at least 95% of it can be assayed after the indicated period of time, or if at least 98.5% of it can be assayed after the indicated period of time. Another measure for stability is the formation of impurities that are degradation products of the substance of general formula (I). A solution can be said to be stable if less than 1 % impurities can be assayed after the indicated period of time. Analytical HPLC methods are preferred to assay active ingredients or impurities, preferably HPLC methods as described in the examples. Therefore, in preferred embodiments of this aspect is provided the composition according to the invention, wherein the substance of general formula (I) or the pharmaceutically acceptable salt thereof is still present at at least 95%, preferably 96%, more preferably 97%, most preferably 98%, 99%, or 99.5% of its original concentration after the indicated period of time, preferably after at least 14 days.

[0077] Alternately, stability can refer to the consistency of the particle size distribution (PSD). In preferred embodiments, a composition is said to be stable if the span does not exceed 4, preferably does not exceed 3, more preferably does not exceed 2.7, even more preferably does not exceed 2.5, most preferably does not exceed 2.3 after the indicated period of time. In preferred embodiments, a composition is said to be stable if the Dv90 remains within about 80-120%, more preferably 90-1 10%, still more preferably 95-105% of its original value after the indicated period of time.

[0078] Provided is a method for treating, preventing, and / or suppressing symptoms of schizophrenia, schizoaffective disorders, and / or Parkinson's disease, wherein the method comprising the step of administering to a subject a composition as defined above. Similarly, the composition as defined above is provided, for use as a medicament. The medicament is preferably for treating, preventing, and / or suppressing symptoms of schizophrenia, schizoaffective disorders, and / or Parkinson's disease. Preferred compositions according to the invention are pharmaceutical compositions.

[0079] Compositions according to the invention are preferably formulated as an injectable composition, either for subcutaneous, intravenous, or intramuscular administration, or as a solution for oral administration, or as a liquid-filled capsule, preferably a softgel capsule. Injectable compositions are preferred. Thus the composition according to the invention may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose container, optionally with an added preservative although preferably without any further additives. In preferred embodiments the composition according to the invention is loaded in a syringe barrel. In preferred embodiments the composition is for use as a medicament, wherein the medicament is administered via parenteral administration. Examples of parenteral administration routes are intradermal, subcutaneous, intramuscular, Intraperitoneal, intrathecal, and intravenous injection, preferably intradermal, subcutaneous, intramuscular, and intrathecal injection, more preferably intramuscular or intrathecal, most preferably intramuscular injection.

[0080] Pharmaceutical compositions which can be administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. These capsules are referred to as softgel capsules. Stabilizers may be added. All formulations for oral administration are preferably in dosages suitable for such administration. Generally speaking, such types of formulation are known in the art, and a skilled person will be able to use the composition according to the invention to obtain such formulations.

[0081] The invention provides the composition according to the invention, for use as a medicament, preferably for treatment of psychosis, schizophrenia, schizoaffective disorders, and / or Parkinson's disease. Psychosis is an abnormal condition of the mind. Subjects suffering from psychosis may exhibit personality changes and thought disorder. Depending on its severity, this may be accompanied by unusual or bizarre behavior, as well as difficulty with social interaction and impairment in carrying out daily life activities. The first-line treatment for many psychotic disorders is antipsychotic medication. Piperazine-benzazepines such as clozapine are known as atypical antipsychotic medication. They are mainly used for treatment of more severe forms of psychosis, such as schizophrenia that does not improve following the use of other antipsychotic medications. In subjects suffering from schizophrenia and schizoaffective disorder, piperazine-benzazepines may decrease the rate of suicidal behavior. A compound for use is preferably for the treatment, amelioration, delay, cure, or stabilization of psychosis, preferably in a subject in need thereof. The use preferably comprises administration of an effective dose of a composition for use according to the invention to a subject in need thereof. Preferably, this aspect provides the composition according to the invention, for treatment of psychosis, wherein psychosis is preferably schizophrenia or psychosis caused by Parkinson’s disease.

[0082] Within this aspect, preferred embodiments provide the composition for use according to the invention, wherein the composition is for administration, preferably in a daily dose of at least 6 mg. For treatment of psychosis associated with Parkinson’s disease, doses of 6.25 to 12.5 mg per day are suitable. For treatment of other forms of psychosis, doses of 400 mg per day are suitable. For severe psychosis, doses of 1000-1200 mg per day are suitable. In preferred embodiments, the composition for use according to the invention is for administration in a daily dose of at least 6 mg and at most 1200 mg. In preferred embodiments, the composition for use according to the invention is for treatment of psychosis associated with Parkinson’s disease, and is for administration in a daily dose of about 6.25 mg to about about 12.5 mg. In preferred embodiments, the composition for use according to the invention is for treatment of psychosis not associated with Parkinson’s disease and is for administration in a daily dose of at least about 400 mg and at most about 1200 mg. In preferred embodiments, the composition for use according to the invention is for treatment of severe psychosis and is for administration in a daily dose of at least about 1000 mg and at most about 1200 mg. In preferred embodiments, the composition for use according to the invention is for treatment of non-severe psychosis and is for administration in a daily dose of at least about 300 mg and at most about 500 mg.

[0083] Within this aspect, preferred embodiments provide the composition for use according to the invention, wherein the composition is for administration at least one time per day. Preferred administration is a regime comprising two doses, a so-called morning dose and a so-called evening dose. Accordingly, preferred embodiments provide the composition for use according to the invention, wherein the composition is for administration at least two times per day. Generally, an evening dose comprises more substance of general formula (I) or a pharmaceutically acceptable salt thereof than a morning dose. Further preferred embodiments provide the composition for use according to the invention, wherein the use is for treatment of psychosis not associated with Parkinson’s diseases, and the composition is for administration two times per day. Further preferred embodiments provide the composition for use according to the invention, wherein the use is for treatment of psychosis associated with Parkinson’s diseases, and the composition is for administration one time per day.

[0084] Further considerations related to the dosage of clozapine are known to a skilled person. Further details regarding ways of administration are known and customary in the art and for instance described in Remington; The Science and Practice of Pharmacy, 21st Edition 2005, University of Sciences in Philadelphia.

[0085] General Definitions

[0086] In this document and in its claims, the verb "to comprise" and its conjugations is used in its nonlimiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the elements are present, unless the context clearly requires that there be one and only one of the elements. The indefinite article "a" or "an" thus usually means "at least one". The word “about” or “approximately” when used in association with a numerical value (e.g. about 10) preferably means that the value may be the given value more or less 1 % of the value.

[0087] Pharmaceutically acceptable salts are known in the art. A skilled person can determine which salts are acceptable. See for example Stahl & Wermuth, ed. “Pharmaceutical Salts: Properties, Selection, and Use” Wiley & sons, 2002, ISBN-13 978-3-90639026-0.

[0088] Whenever a parameter of a substance is discussed in the context of this invention, it is assumed that unless otherwise specified, the parameter is determined, measured, or manifested under physiological conditions. Physiological conditions are known to a person skilled in the art, and comprise aqueous solvent systems, atmospheric pressure, pH-values between 6 and 8, a temperature ranging from room temperature to about 37 °C (from about 20 °C to about 40 °C), and a suitable concentration of buffer salts or other components. It is understood that charge is often associated with equilibrium. A moiety that is said to carry or bear a charge is a moiety that will be found in a state where it bears or carries such a charge more often than that it does not bear or carry such a charge. As such, an atom that is indicated in this disclosure to be charged could be non-charged under specific conditions, and a neutral moiety could be charged under specific conditions, as is understood by a person skilled in the art.

[0089] In the context of this invention, a decrease or increase of a parameter to be assessed means a change of at least 5% of the value corresponding to that parameter. More preferably, a decrease or increase of the value means a change of at least 10%, even more preferably at least 20%, at least 30%, at least 40%, at least 50%, at least 70%, at least 90%, or 100%. In this latter case, it can be the case that there is no longer a detectable value associated with the parameter.

[0090] The use of a substance as a medicament as described in this document can also be interpreted as the use of said substance in the manufacture of a medicament. Similarly, whenever a substance is used for treatment or as a medicament, it can also be used for the manufacture of a medicament for such treatment. Products for use as described herein are suitable for use in methods of treatment or of diagnosis as described herein.

[0091] The present invention has been described above with reference to a number of exemplary embodiments. Modifications and alternative implementations of some parts or elements are possible, and are included in the scope of protection as defined in the appended claims. Each embodiment as identified herein may be combined together unless otherwise indicated. All citations of literature and patent documents are hereby incorporated by reference.

[0092] Description of drawings

[0093] Fig. 1A - Overlay of the particle size distribution (PSD) at the different milling time intervals of composition #4 (buffered at pH 8 and containing 20 mg / g P338) up to 10h milling. Fiq. 1 B - Overlay of the PSD at the different milling time intervals of composition #4 (buffered at pH 8 and containing 20 mg / g P338 up to 10h milling; and 50 mg / g P338 from 10h up to 27h milling) from 10h up to 27h milling.

[0094] Fiq. 1 C - Overlay of the PSD at the different milling time intervals of composition #8 (buffered at pH 8 and containing 20 mg / g P338 and 50 mg / g Mannitol) up to 10h milling.

[0095] Fiq. 1 D - Overlay of the PSD at the different milling time intervals of composition #8 (buffered at pH 8 and containing 20 mg / g P338 and 50 mg / g Mannitol up to 10h milling; and 35 mg / g P338 and 50 mg / g Mannitol from 10h up to 27h milling) from 10h up to 27h milling.

[0096] Fiq. 2A - Second NS screening, bead milling part 1 - Overlay of the PSD at the different milling time intervals of composition with 30 mg / g P338 - pH 8 (composition #12).

[0097] Fiq. 2B - Second NS screening, bead milling part 1 - Overlay of the PSD at the different milling time intervals of composition with 50 mg / g P338 - pH 8 (composition #14).

[0098] Fiq. 2C - Second NS screening, bead milling part 1 - Overlay of the PSD at the different milling time intervals of composition with 30 mg / g P338 - pH 7.5 (composition #16).

[0099] Fiq. 3A - Second NS screening, bead milling part 2 - Overlay of the PSD at the different milling time intervals of composition with 30 mg / g P338 - pH 8 (composition #12), wherein the batch is different from bead milling part 1.

[0100] Fiq. 3B - Second NS screening, bead milling part 2 - Overlay of the PSD at the different milling time intervals of composition with 50 mg / g P338 - pH 8 (composition #14), wherein the batch is different from bead milling part 1.

[0101] Fiq. 3C - Second NS screening, bead milling part 2 - Overlay of the PSD at the different milling time intervals of composition with 30 mg / g P338 - pH 7.5 (composition #16), wherein the batch is different from bead milling part 1.

[0102] Fiq. 4A -Overlay of the PSD of duplicate suspensions of composition #12 after 4h (NS screening II bead milling part 1) and 24h (NS screening II bead milling part 2) milling before and after overnight storage at 2-8°C.

[0103] Fiq. 4B - Overlay of the PSD of duplicate suspensions of composition #14 after 4h (NS screening II bead milling part 1) and 24h (NS screening II bead milling part 2) milling before and after overnight storage at 2-8°C.

[0104] Fiq. 4C - Overlay of the PSD of duplicate suspensions of composition #16 after 4h (NS screening II bead milling part 1) and 24h (NS screening II bead milling part 2) milling before and after overnight storage at 2-8°C.

[0105] Fiq. 5A - Overlay of the PSD at 8h and 20h comparing Rep 1 (Second NS screening, bead milling part 1) to Rep 2 (Second NS screening, bead milling part 2) of composition #12.

[0106] Fiq. 5B - Overlay of the PSD at 8h and 20h comparing Rep 1 (Second NS screening, bead milling part 1) to Rep 2 (Second NS screening, bead milling part 2) of composition #14.

[0107] Fiq. 5C - Overlay of the PSD at 8h and 20h comparing Rep 1 (Second NS screening, bead milling part 1) to Rep 2 (Second NS screening, bead milling part 2) of composition #16. Examples

[0108] Example 1 - Solubility screening

[0109] This example describes the solubility experiments performed on drug substance (DS), in this case clozapine. In a first part, the solubility of clozapine was determined in aqueous and buffered media at different pH values and aqueous solutions of excipients. In a second part, the most promising excipients were tested in buffered media at pH 7 and 8. Moreover, different buffer concentrations were evaluated. Solubility determination of clozapine was performed via HPLC analysis as described in this application.

[0110] Material & Methods Table 2 - Consumables and reagents used during the solubility screening Preparation of Solubility screening I

[0111] The following media were prepared

[0112] A. 0.1 % (w / v) excipient solutions:

[0113] Weigh 50 mg (± 10 %) of the excipient into a suitable glass beaker. Fill with approximately 80 % of water (Type II) and stir until dissolved. Transfer the solution to a 50 mL volumetric flask and dilute to volume with water (Type II) and homogenize.

[0114] B. 0.2 % (w / v) excipient solutions:

[0115] Weigh 100 mg (± 10 %) of the excipient into a suitable glass beaker. Fill with approximately 80 % of water (Type II) and stir until dissolved. Transfer the solution to a 50 mL volumetric flask and dilute to volume with water (Type II) and homogenize.

[0116] C. 0.5 % (w / v) excipient solutions:

[0117] Weigh 125 mg (± 10 %) of the excipient into a suitable glass beaker. Fill with approximately 80 % of water (Type II) and stir until dissolved. Transfer the solution to a 25 mL volumetric flask and dilute to volume with water (Type II) and homogenize. Weigh 250 mg of the excipient into a suitable glass beaker. Fill with approximately 80 % of water (Type II) and stir until dissolved. Transfer the solution to a 50 mL volumetric flask and dilute to volume with water (Type II) and homogenize. (Only used for the PEG3350 solution).

[0118] D. 1 % (w / v) excipient solutions:

[0119] Weigh 250 mg (± 10 %) of the excipient into a suitable glass beaker. Fill with approximately 80 % of water (Type II) and stir until dissolved. Transfer the solution to a 25 mL volumetric flask and dilute to volume with water (Type II) and homogenize.

[0120] E. 1 .5 % (w / v) excipient solutions:

[0121] Weigh 375 mg (± 10 %) of the excipient into a suitable glass beaker. Fill with approximately 80 % of water (Type II) and stir until dissolved. Transfer the solution to a 25 mL volumetric flask and dilute to volume with water (Type II) and homogenize.

[0122] F. 2.5 % (w / v) excipient solutions:

[0123] Weigh 625 mg (± 10 %) of the excipient into a suitable glass beaker. Fill with approximately 80 % of water (Type II) and stir until dissolved. Transfer the solution to a 25 mL volumetric flask and dilute to volume with water (Type II) and homogenize.

[0124] G. 5 % (w / v) excipient solutions:

[0125] Weigh 1250 mg (± 10 %) of the excipient into a suitable glass beaker. Fill with approximately 80 % of water (Type II) and stir until dissolved. Transfer the solution to a 25 mL volumetric flask and dilute to volume with water (Type II) and homogenize.

[0126] H. 50 mM citrate buffer pH 5:

[0127] Weigh 0.36 g (± 10 %) citric acid monohydrate and 0.97 g (± 10 %) sodium citrate dihydrate into a 100 mL volumetric flask. Add approximately 80 % water (Type II) and stir until dissolved. Afterwards, dilute to volume with water (Type II), homogenize and verify the pH.

[0128] I. 50 mM citrate buffer pH 6:

[0129] Weigh 0.11 g (± 10 %) citric acid monohydrate and 1.32 g (± 10 %) sodium citrate dihydrate into a 100 mL volumetric flask. Add approximately 80 % water (Type II) and stir until dissolved. Afterwards, dilute to volume with water (Type II), homogenize and verify the pH.

[0130] J. 50 mM phosphate buffer pH 6:

[0131] Weigh 0.10 g (± 10 %) disodium hydrogen phosphate dihydrate and 0.69 g (± 10 %) sodium dihydrogen phosphate dihydrate into a 100 mL volumetric flask. Add approximately 80 % water (Type II) and stir until dissolved. Afterwards, dilute to volume with water (Type II), homogenize and verify the pH.

[0132] K. 50 mM phosphate buffer pH 7:

[0133] Weigh 0.50 g (± 10 %) disodium hydrogen phosphate dihydrate and 0.34 g (± 10 %) sodium dihydrogen phosphate dihydrate into a 100 mL volumetric flask. Add approximately 80 % water (Type II) and stir until dissolved. Afterwards, dilute to volume with water (Type II), homogenize and verify the pH.

[0134] L. 50 mM phosphate buffer pH 7.5:

[0135] Weigh 0.71 g (± 10 %) disodium hydrogen phosphate dihydrate and 0.15 g (± 10 %) sodium dihydrogen phosphate dihydrate into a 100 mL volumetric flask. Add approximately 80 % water (Type II) and stir until dissolved. Afterwards, dilute to volume with water (Type II), homogenize and verify the pH.

[0136] M. 50 mM phosphate buffer pH 8:

[0137] Weigh 0.83 g (± 10 %) disodium hydrogen phosphate dihydrate and 0.06 g (± 10 %) sodium dihydrogen phosphate dihydrate into a 100 mL volumetric flask. Add approximately 80 % water (Type II) and stir until dissolved. Afterwards, dilute to volume with water (Type II), homogenize and verify the pH.

[0138] Solubility of clozapine in different excipient solutions was screened at two concentration levels (low high) in view of formulation development. Aqueous media containing excipients were prepared weight to volume (w / v) using purified water (type II). Moreover, several buffer solutions (50 mM strength) were included in the screening to investigate the effect of pH on clozapine solubility.

[0139] The following excipients were tested: Tween 20 (0.5 % and 2.5 %, w / v), Tween 80 (0.5 % and 2.5 %, w / v), DOSS (0.1 % and 1.5 %, w / v), Kolliphor ELP (0.5 % and 2.5 %, w / v), Kolliphor P188 (0.5 % and

[0140] 2.5 %, w / v), PvP K30 (1 % and 5 %, w / v), Kolliphor P338 (0.5 % and 2.5 %, w / v), Lecithin (0.2 % and

[0141] 1 .5 %, w / v), PEG 3350 (0.5 % and 5 %, w / v), Mannitol (1 % and 5 %, w / v), Sorbitol (1 % and 5 %, w / v), Citrate buffer pH 5, Citrate buffer pH 6, Phosphate buffer pH 6, Phosphate buffer pH 7, Phosphate buffer pH 7.5, Phosphate buffer pH 8, Purified water (Type I)

[0142] Preparation of Solubility screening II

[0143] Four phosphate buffer stock solutions are prepared at twice the molarity targeted in the final media solution. The composition of these stock solutions is given in Table 3. The buffer components are dissolved in purified water type II using volumetric flasks. After homogenization, the pH of the solution is checked. The batch scale applied varies from 50 to 500 mL. Table 3. Composition of the buffer stock solutions used to prepare the media at pH 7 or pH 8 with most promising excipients from Solubility screening I.

[0144] A. 0.1 % (w / v) excipient solutions in 5 mM phosphate buffer (pH 7 and pH 8):

[0145] Transfer 25 mL of buffer stock solution to a 50 mL volumetric flask. Weigh 50 mg (± 10 %) of the excipient into the 50 mL volumetric flask. Fill to approximately 80 % of total volume using water (Type II) and stir until dissolved. Dilute to volume with water (Type II), homogenize and verify pH.

[0146] B. 0.5 % (w / v) excipient solutions in 5 mM phosphate buffer (pH 7 and pH 8):

[0147] Transfer 12.5 mL of buffer stock solution to a 25 mL volumetric flask. Weigh 125 mg (± 10 %) of the excipient into a 25 mL volumetric flask. Fill to approximately 80 % of total volume using water (Type II) and stir until dissolved. Dilute to volume with water (Type II), homogenize and verify pH.

[0148] C. 2.5 % (w / v) excipient solutions in 5 mM phosphate buffer (pH 7 and pH 8):

[0149] Transfer 12.5 mL of buffer stock solution to a 25 mL volumetric flask. Weigh 625 mg (± 10 %) of the excipient into a 25 mL volumetric flask. Fill to approximately 80 % of total volume using water (Type II) and stir until dissolved. Dilute to volume with water (Type II), homogenize and verify pH.

[0150] D. 15 mM phosphate buffer pH 7 and pH 8:

[0151] Transfer 12.5 mL of buffer stock solution to a 25 mL volumetric flask. Dilute to volume with water (Type II), homogenize and verify pH.

[0152] In the second solubility screening, buffered media (5 mM strength) containing the most promising excipients from solubility screening I were evaluated at both pH 7 and pH 8. Buffered media containing excipients were prepared weight to volume (w / v). Moreover, buffer solutions at 5 mM and 15 mM concentration were tested as well to evaluate the impact of the ionic strength on the solubility of clozapine.

[0153] The following compositions were tested: Kolliphor P188 (0.5 %, w / v) in phosphate buffer pH 7 (5 mM), Kolliphor P338 (2.5 %, w / v) in phosphate buffer pH 7 (5 mM), DOSS (0.1 %, w / v) in phosphate buffer pH 7 (5 mM), Kolliphor P188 (0.5 %, w / v) in phosphate buffer pH 8 (5 mM), Kolliphor P338 (2.5 %, w / v) in phosphate buffer pH 8 (5 mM), DOSS (0.1 %, w / v) in phosphate buffer pH 8 (5 mM), Phosphate buffer pH 7 (5 mM), Phosphate buffer pH 8 (5 mM), Phosphate buffer pH 7 (15 mM), Phosphate buffer pH 8 (15 mM).

[0154] Solubility testing

[0155] Solubility testing of the samples was performed at room temperature (protected from light), by tumbling at 20 RPM using a Labinco rotary mixer (head-over-head tumbling) and three 4 mm glass beads to optimize dispersion by influencing the hydrodynamics.

[0156] To start solubility testing, 6 mL of medium was added to test glass tubes containing 12 mg of the DS batch A-170577 (approximately targeting 2 mg / mL clozapine). Glass test tubes were capped with Bottger Blue HDPE caps and sealed with parafilm. Each medium was tested in duplicate.

[0157] After 24 hours of tumbling, 2 mL of sample was taken and centrifuged at 24 400 g for 10 minutes. Subsequently, the supernatant was adequately diluted with water (Type l) / MeOH (20 / 80, v / v) in order to have a sample solution concentration within the linear range of the HPLC method (approximately 1 mg / mL clozapine) and the remaining amount of supernatant was transferred to a glass test tube and stored overnight (i.e. 48 hours) at room temperature. If new sedimentation (i.e. new equilibrium) was formed after 48 hours, samples were centrifuged again and solubility determination was performed on the supernatant as described for the 24 hours time point. For solubility screening II, no remaining supernatant after 24 hours tumbling was stored overnight for 48 hours analysis.

[0158] The pH was measured prior to solubility testing and after 24 hours (and 48 hours in case of sedimentation) of tumbling by means of a pH meter. Also, visual observations were reported at the start of the solubility experiment and after 24 and 48 hours. pH measurement

[0159] A pH meter Seven Easy (Mettler Toledo) with an InLab® Expert pro electrode or a Metrohm 913 pH meter with a Solitrode LL electrode was used to measure the pH. After performing a three-point calibration (buffers with pH 2.00, 4.01 and 9.21 , verification with 5.00 (Expert pro) and 3.00 and 7.00 (Solitrode)), the pH was determined before and 24 hours (and 48 hours in case of new sedimentation) after adding the drug substance when performing the solubility test. This methodology is based on Chapter 2.2.3 Potentiometric determination of pH, European Pharmacopoeia.

[0160] HPLC analysis of solubility samples

[0161] An HPLC instrument method for the concentration determination of clozapine in solubility testing samples is described in Table 4. This method is based on gradient reversed-phase separation with UV detection. The test method can also be used for the identification of clozapine in these samples based on retention time comparison with a certified reference standard. Table 4 - Instrumental conditions for the solubility method

[0162] 1A system or column is considered equivalent as long as system suitability test (SST) criteria are met and a comparable separation of all relevant compounds is achieved.

[0163] 2The injection volume may be adjusted to increase or decrease the detector response as long as both parameters fall within the qualified range defined during testing, and as long as SST criteria are met and a comparable separation of all relevant compounds is achieved.

[0164] Clear glass ware and selective yellow light not emitting any other light in the UV and not emitting light of the blue part of the UV-VIS spectrum was used to prepare reference and sample solutions (Table 5). Table 5 - Preparation reference and sample different amounts or volumes may be used as long as the final concentration remains the same.

[0165] Note 1 : All sample solutions, meant for injection on a HPLC system were centrifuged for 10 minutes at 24 400 g prior to injection

[0166] Note 2: Samples exceeding the concentration of reference solution 1 (100 %) with more than 20 % were diluted with dilution solvent towards a concentration in a range within 1 - 120 % of the concentration of reference solution 1 .

[0167] Note 3: Samples which were turbid after centrifugation or dilution were filtered before injection. In this case a 0.2 pm PVDF (Polyvinylidene fluoride) filter (13 mm internal diameter) was used. The filter was presaturated with 0.5 mL of the sample solution prior to collection in a HPLC vial.

[0168] For the concentration determination of clozapine, the injection sequence and system suitability testing criteria as shown in Table 6 were applied.

[0169] Table 6 - Injection sequence and system suitability testing criteria Note: Maximum 12 injections of sample solutions between bracketing of reference solution 1 (100 %).

[0170] For the concentration determination of clozapine, the following equation was used:

[0171] Concentration API (mg / mL) = ( rsx crx Pr) / ( F’rx rr), wherein

[0172] Pr = purity (< 1 .000) of the reference product (or 1 / correction factor* if correction factor (> 1 .00) available) F’r = salt / base factor of the reference product (if applicable)* rs= peak area of the clozapine peak in the sample solution rr= average peak area (n = 5) of clozapine in reference solution 1 (calibration) cr= concentration (mg / mL) of reference solution 1 (clozapine)

[0173] *Note that sometimes the Purity factor and the Salt / Base factor can already be implemented and merged in a correction factor described in the CoA. Hereby in the CoA, it should be stated how the correction factor is calculated.

[0174] To calculate the recovery of a compound in reference solutions, the following equation was used:

[0175] Recovery API (%) = S x ( rd rr) x ( qr / qc) x 100, wherein

[0176] S = scaling factor (S = 1 for reference solution 1 and 2, and S = 100 for reference solution 3) rc= peak area of clozapine in reference solution 1 (control or final), 2 or 3 qr= weighed amount (mg) of reference product (powder batch) in reference solution 1 (clozapine) qc= weighed amount (mg) of reference product (powder batch) in reference solution 1 or 2 (clozapine)

[0177] The compound identification of clozapine complies with the SST acceptance criteria described in Table 6. This method has been tested with DS batch A-170577. The retention time of clozapine in reference solution 1 (100 %) as could be derived from the chromatogram (data not shown) is 8.58 minutes. Small retention time deviations can be observed, mainly when using different HPLC systems. However, the elution profile of clozapine should be clear concerning identification.

[0178] The solubility classification system applied to the tested samples is shown in Table 7.

[0179] Table 7 - Ph. Eur. General Notices Solubility classification

[0180] Results Solubility screening I

[0181] The solubility of clozapine was investigated in different buffered media and excipient solutions in water (Type II), in function of pharmaceutical development of a nanosuspension. The solubility was performed at a concentration of approximately 2 mg / mL clozapine. Results can be found in Tables 8-11 .

[0182] Table 8 - Solubility of clozapine in different media / buffers

[0183] As shown in Table 8, clozapine is practically insoluble to slightly soluble in all tested media, except in citrate buffer pH 5 (solubility > 2 mg / mL). Table 8 further shows that a buffer is needed to maintain pH stability, as ApH is 2.09 in purified water. Also, a phosphate buffer is preferred over a citrate buffer, as the solubility of clozapine is lower in a phosphate buffer compared to a citrate buffer of the same pH (pH 6), and a phosphate buffer of pH 7-8 results in a lower clozapine solubility in comparison to a phosphate buffer of pH 6. Of note, no clear conclusions of solubility in phosphate buffer pH 7 could be made due to high variability between replicates, and solubility evaluation was repeated in a second solubility screening. Finally, pH remained stable in buffered media after 24 hours solubility testing and a decreasing trend in solubility of clozapine was noticed from low to high pH.

[0184] Table 9 - Solubility of clozapine using different surfactants

[0185] In aqueous media, an increment (> 0.7 units) in pH was observed after 24h solubility testing for all excipient solutions, which decreased after 48h (note that only supernatant of 24 hours samples was stored till 48 hours and therefore sediment was removed), see Table 9. Table 9 also shows that Kolliphor P188, Kolliphor P388 and DOSS 0.1% are superior over other surfactants in terms of solubility, as they result in a solubility lower than 0.10 mg / mL. For Kolliphor P188 and Kolliphor P388, this was the case at both the lower and higher concentration. Kolliphor P188 and Kolliphor P338 (at both concentrations) also yield smaller variations in pH as compared to DOSS 1 .5%. In most cases, solubility after 48 hours remained practically constant compared to 24 hours, except in DOSS at 1 .5 % and in lecithin at 0.2 where a lower solubility was measured after 48 hours.

[0186] Table 10 - Solubility of clozapine using suspending agents

[0187] Table 11 - Solubility of clozapine using tonicifiers

[0188] Whereas a solubility enhancing effect was observed using a higher concentration of surfactants and suspending agents in all cases (Table 9 and 10), no changes in solubility were observed using the tonicifiers (Table 11).

[0189] In view of nanosuspensions, a solubility below 0.10 mg / mL clozapine was obtained for:

[0190] • DOSS at 0.1 % (w / v)

[0191] • Kolliphor P188 and Kolliphor P338 from 0.5 % (w / v) up to 2.5 % (w / v)

[0192] • PEG 3350 from 0.5 % (w / v) up to 5 % (w / v)

[0193] • Mannitol and sorbitol from 1 % (w / v) up to 5 % (w / v)

[0194] • Phosphate buffer pH 8 (50 mM)

[0195] Based on these results, a second solubility screening was performed including the most promising excipients (i.e. DOSS, Kolliphor P188 and Kolliphor P338) in buffered media at pH 7 and pH 8. The tonicifiers (PEG 3350, Mannitol and Sorbitol) were not included in the second solubility screening since they are further evaluated during the nanosuspension screening.

[0196] Results Solubility screening II

[0197] In a second solubility screening, the most promising excipients were tested in buffered media at pH 7 and 8. Moreover, different buffer concentrations (5 and 15 mM) were evaluated. The solubility was performed at a concentration of approximately 2 mg / mL clozapine. The results are shown in Table 12 and 13.

[0198] Table 12 - Evaluation of buffer concentrations

[0199] Table 13 - pH stability and clozapine solubility

[0200] As shown in Table 12 and 13, clozapine is practically insoluble to very slightly soluble in all tested solubility media. At both pH 7 and pH 8, a slight decrease in solubility was measured when decreasing buffer molarity (Table 12).

[0201] Targeted solubility, i.e. below 0.10 mg / mL clozapine, was obtained for the following compositions:

[0202] • DOSS at 0.1 % (w / v) in buffer pH 7 • Kolliphor P188 at 0.5 % (w / v) in buffer pH 7 and 8

[0203] • Kolliphor P388 at 2.5 % (w / v) in buffer pH 8

[0204] • Phosphate buffer pH 7 (5 and 15 mM) and pH 8 (5, 15, and 50 mM)

[0205] Finally, pH remained stable after 24h solubility testing in all six tested compositions except for DOSS (an increase of approximately 1 pH unit was observed for both buffered solutions containing 0.1 % (w / v) DOSS).

[0206] Example 2 - Development of a clozapine suspension This report describes the screening study for a potential Clozapine liquid formulation, suitable for administration via intra-muscular injection in pre-clinical studies and Phase I clinical trials. Formulation development of Clozapine as a nanosuspension at 50 mg / g was performed, using the most promising excipients of Example 1.

[0207] Materials & Methods

[0208] In Table 14-16, an overview is provided of the used products, consumables and instruments.

[0209] Table 14 - Overview of used products

[0210] Table 15 -Overview of used consumables

[0211] Table 16 - Overview of used instruments

[0212] Ns (nanosuspension) preparation

[0213] Samples were prepared on weight (w / w) for all components (purified water, API (active pharmaceutical ingredient), surfactant(s) / stabilizer(s) and grinding beads) in 20 mL glass vials (clear glass Type I) used as grinding container. Ns with an API content of 50 mg / g (correction factor (CF) not taken into account) were prepared at 5 g scale.

[0214] First, a concentrated phosphate buffer stock solution was prepared (see section Phosphate buffer stock solutions'). Next the excipients were dissolved in purified water and then diluted using the phosphate buffer stock solutions. In order to reach the target concentrations in the final suspension these stabilizer solutions contained an overage of excipients.

[0215] Meanwhile, grinding beads and API were weighed and added to the vial. Zirconium oxide grinding beads (Yttrium stabilized) with a diameter of 1 mm were used at 18 g per vial. Subsequently, the stabilizer solution was added to the vial. The vial was closed using a bromobutyl stopper and aluminum crimp cap. Before starting the milling process, the grinding container was tumbled 10 times.

[0216] Low shear milling was performed using a Peira (Beerse, Belgium) roller mill. The rolling speed of the vials was set at 160 rpm. Samples were taken at different time points in order to determine the particle size evolution during milling. After the milling process, the Ns were harvested (i.e. separated from the milling beads) using a 1 mL syringe with a 23G needle. Phosphate buffer stock solutions

[0217] Two phosphate buffer stock solutions are prepared at twice the molarity targeted in the final nanosuspension. The composition of these stock solutions is given in Table 17. The buffer components are dissolved in purified water type II using volumetric flasks. After homogenization, the pH of the solution is checked. The batch scale applied varies from 100 to 500 mL.

[0218] Table 17 - Composition of the buffer stock solutions used to prepare the stabiliser solutions at pH 7.5 or 8.0

[0219] Appearance

[0220] Visual inspection of the suspension was performed in a lab illuminated with white or halogen light. A maximum distance of 50 cm between the eye and the item to be inspected was respected. The whole surface of the object was inspected, and the necessary observation time was taken to check the presence of yellow particles. Samples were observed for at least 5 seconds against a black and white background (Apollo 2 Liquid Viewer, Adelphi). pH measurements

[0221] The pH of the samples was determined using a pH meter (Mettler Toledo Seven Compact S220 pH meter and an InlabOMicro electrode or a Metrohm 913 pH meter and a Solitrode LL electrode) calibrated with a three-point calibration and two-points verification. The samples were left to equilibrate at room temperature (RT, ± 22°C) before the pH was measured.

[0222] Laser diffraction measurements

[0223] All laser diffraction (LD) measurements were performed using a Mastersizer 3000 (Malvern, UK) equipped with a HydroMV wet dispersion unit. Each analysis consisted of at least 5 consecutive measurements of the same sample. The particle size was expressed via the volume diameter (Dv) using ‘Mastersizer v3.60.’ software. The refractive index of the particles and the dispersion medium were set to 1.64 and 1.33, respectively. The absorption index of the particles was set to 0.001.

[0224] In case the variation in Dv10, Dv50 and Dv90 was less than or equal to 5% over subsequent measurements, the reported diameters were the average of the subsequent measurements. In case the variation in Dv10, Dv50 and Dv90 was more than 5% over subsequent measurements, a regression analysis was performed on these diameters in function of time. If a significant particle size increase or decrease was observed on a 5% significance level, diameters of the first measurements were reported in most cases, as the observed trend was expected to be due to the manipulation of the sample required for LD measurements. As such, the first measurement should be most representative for the sample before dilution.

[0225] Osmolality

[0226] Samples were measured using the Advanced® Micro-Osmometer Model 3320 (Advanced Instruments), calibrated with a two-points calibration (50 mOsm / kg and 850 mOsm / kg, n = 3) and verified with a 290 mOsm / kg standard (n = 3). The samples were first left to equilibrate at room temperature (RT, ± 22°C). Before each measurement, the measurement cell was cleaned with a dry chamber cleaner and a new sampler tip was used for each sample. Samples were measured once.

[0227] Assay / Purity

[0228] Assay and chromatographic purity determination was carried out according to the analytical method described in M-P14001 -001 v1.0 (Eurofins Amatsigroup NV). The assay determination was performed in duplicate (n=2), whereby the purity profile determination was performed only on the first replicate.

[0229] Impurities or degradants present in the samples were named according to their relative retention time (RRT). Quantification of clozapine, impurities or degradants were performed by weight / weight (w / w) (assay %). The reporting threshold for the impurities was set to 0.05% w / w.

[0230] Results

[0231] First NS screening

[0232] A first nanoscreening via bead milling was performed evaluating several stabilizers (i.e. DOSS, P188, P338 and Kollidon 30) at different concentrations. Table 18 tabulates the composition of the suspensions which were prepared at 50 mg / g clozapine. A pH between 7 and 8 at a molarity of 5 or 10 mM was assessed. The incorporation of a tonicifier (Mannitol) was evaluated as the DP is intended to be administered by IM injection.

[0233] T able 18 - Overview of the composition of the tested clozapine suspensions

[0234] 1Clozapine batch A-170577 was used. No CF was applied.

[0235] Samples were harvested after 32 hours milling and stored for 1 week at 2-8°C. The results of the particle size distribution after harvesting are gathered in Table 19. Although the laser obscuration remained stable (i.e. < 5% variation over subsequent measurements), the variation in particle size exceeded the 5% between consecutive measurements and in some cases a trend was observed over subsequent measurements. The laser diffraction device might influence stability of the samples.

[0236] Table 19 - Particle size distribution after harvesting the 50 mg / g clozapine nanosuspension compositions 1First measurement of five reported (variability > 5% between consecutive measurements and trend observed over subsequent measurements)

[0237] 2Average measurement of five reported

[0238] Next to particle size measurement via laser diffraction, pH and assay purity (A / P) were analyzed on all compositions. The results are gathered in Table 20. In addition, the osmolality of composition #8 was measured resulting in 368 mOsm / kg, which is acceptable for IM injection.

[0239] Concerning pH, a stable pH was obtained for the compositions containing 20 mg / g Kolliphor P338 both at pH 8 and pH 7.5 except when combined with DOSS at pH 7. No difference in pH shift was measured when increasing the buffer molarity from 5 to 10 mM (i.e. Composition #4 compared to #6). Nevertheless, a pH shift > 0.2 was measured for the compositions containing Kolliphor P188 indicating an insufficient buffer capacity to stabilize the clozapine particles after milling.

[0240] The compositions containing 20 mg / g Kolliphor P338, except when combined with DOSS (i.e. compositions #4, -F, -G, -H, -J and -K) displayed acceptable assay values ranging between 90 and 110%. Note that for composition #6 a mean assay of 89.6% was measured which is slightly below the standard lower limit of 90%. For all other compositions, low clozapine assays (< 90%) were measured, indicating possible homogeneity issues. The composition containing 5 mg / g Kolliphor P338 (#5) also displayed a slightly lower assay of 85.7%. However, all compositions containing Kolliphor P188 (#1 / B / C / I), except when combined with Kolliphor P338, display low assays below 75%. Finally, similar purity profile was observed for all compositions. Overall, the compositions containing 20 mg / g Kolliphor P338 except when combined with DOSS were most promising.

[0241] Table 20 - Overview of the pH and A / P analysis after harvesting the 50 mg / g clozapine compositions

[0242] Test run

[0243] Based on the particle size measurements after 16h and 32h milling, it was suspected that nanoparticles were reached at a shorter milling time than 16h. To allow a more detailed evaluation of the particle size reduction process it was proposed to perform a test run including only a limited amount of compositions to focus on short milling time intervals.

[0244] Based on the results previously obtained, two compositions were selected to evaluate particle size reduction at short milling time intervals. The first was composition #4, chosen due to presence of nanoparticles after 16h milling, and after 32h milling (Table 19). The second was composition #8. It is essentially the same as the first composition, but further includes Mannitol in view of IM injection (Table 18).

[0245] To assess the milling efficiency of the two compositions, the particle size was measured after 3, 5, 7, 10, 12, 14, 16, 24 and 27 hours milling using laser diffraction to obtain information on the evolution of the particle size distribution. The results are given in Table 21 and overlays of the particle size distributions after different milling times are given in Fig. 1A and 1 B (composition#4) and Fig. 1C and D (composition #8).

[0246] Table 21 - PSD as a function of milling time for 50 mg / g Clozapine compositions

[0247] 1First measurement of five reported (variability > 5% between consecutive measurements and trend observed over subsequent measurements)

[0248] 2Second measurement reported (Air included in first measurement) From 3h milling up to 7h (for #4) or up to 10h (for #8) a broad particle size distribution (indicated by the span value in Table 21) was measured containing very small particles (< 0.1 pm). Presence of very small and very large particles might induce instability in the formulation. After 10h milling particle aggregation (i.e. overmilling) was observed for both compositions. This could be due to a lack of surfactant available to cover the particle surface and stabilize the particles against aggregation. To evaluate this hypothesis the concentration of Kolliphor P338 was increased to 50 mg / g for composition #4 and to 35 mg / g for composition #8 after 10h milling. From 12h milling onwards, a bi- modal distribution was obtained of which the main peak was situated between 1 and 10 pm. A slight shift to the nanorange was noticed at each milling time interval until 27h milling. The particle size reduction seemed to be slightly slower for the concept containing Mannitol (composition #8). Table 22 tabulates the visual evaluation of the compositions at each milling time interval. The main observation here was the change from a yellow suspension to an off-white suspension after 10h milling. The colour change is expected to indicate the presence of agglomerates in the suspension. Table 22 - Overview of the appearance at the different milling time intervals

[0249] Next to the particle size, pH and osmolality were measured after 27h milling. The results are gathered in Table 23 and are in line with previous results.

[0250] Table 23 - Analysis results after 27h milling of the compositions

[0251] The particle size shift to the microrange (i.e. aggregation) after 10h milling is suspected to enhance the stability of the formulation due to the narrow distribution in comparison to the distribution obtained up to 7h milling. For future screenings, a Dv 90 around 5 pm and a span value < 3 is targeted. Based on these results the composition containing Mannitol (#8) was selected for further development.

[0252] Second NS screening - Bead milling part 1

[0253] Based on the results obtained during the first screenings, Kolliphor P338 was believed to have the best stabilizing properties. Therefore, this surfactant was evaluated at several concentrations i.e. 30, 40 and 50 mg / g buffered at both pH 7.5 and pH 8 during a second screening. In addition, the combination with Kolliphor P188 at 2 mg / g was also evaluated. Mannitol at 50 mg / g was included for all compositions to adjust the osmolality to an acceptable value for IM injection. Table 24 - Compositions of the 50 mg / g Clozapine compositions during screening II

[0254] To assess the milling efficiency of the different compositions, particle size was measured after 2, 4, 8 and 20 hours milling using laser diffraction to obtain information on the evolution of the particle size distribution. The results are given Table 25. Up to 8h milling a broad particle size distribution is measured containing very small particles (< 0.1 pm). Presence of very small and very large particles might induce instability in the formulation which is highlighted during laser diffraction measurement. The particle size of compositions #12, #15, #16 increased after overnight storage at 2-8°C. A decrease in particle size was seen for all other compositions. After 20h milling, aggregation (i.e. overmilling) was observed for all compositions and a bi-modal distribution was obtained of which the main peak was situated between 1 and 10 pm. The target Dv 90 value around 5 pm and a span value below 3 was reached for all compositions.

[0255] Table 25 - PSD as a function of time for the 50 mg / g Clozapine compositions

[0256] 1First measurement of five reported

[0257] 2Average measurement of five reported

[0258] 3Storage overnight Visual evaluation of the compositions at each milling time interval indicated a change from a yellow suspension to an off-white suspension between 8h and 20h milling. In addition, it was observed that presence of yellow particles disappeared after 20h milling. The removal of yellow particles indicates that up to 20h milling, the suspension still changed. After 20h milling a homogeneous suspension was obtained.

[0259] Samples were harvested after 20 hours milling. The results of the particle size distribution after harvesting are gathered in Table 26. Although the laser obscuration remained stable i.e. < 5%, the variation in particle size exceeded the 5% between consecutive measurements and in some cases a trend was observed over subsequent measurements. In general, a Dv 10 around 0.1 pm, a Dv 50 around 2.5 pm and a Dv 90 around 5 pm was measured for all compositions after harvesting.

[0260] Table 26 - PSD after harvesting the 50 mg / g Clozapine compositions

[0261] 1First measurement of five reported

[0262] Next to particle size measurement via laser diffraction, appearance, pH, osmolality and A / P were analyzed on all compositions (Table 27). After harvesting, all suspensions can be described as off-white and homogeneous. Concerning pH, a stable pH is obtained for all compositions indicating that 5 mM buffer concentration is sufficient to stabilize the Clozapine particles after milling when formulated both at pH 8 or pH 7.5. The osmolality of all compositions ranges within acceptable limits in view of IM injection i.e. < 600 mOsm / kg. An increasing osmolality is measured with increasing Kolliphor P338 concentration. No difference is measured for the same composition at pH 7.5 or pH 8. No impurities or degradant peaks were detected above reporting threshold in any composition and acceptable clozapine assay values ranging between 90-110% were measured in all cases.

[0263] Table 27 - Overview of analysis results after harvesting 50 mg / g clozapine compositions

[0264] Based on these results 20h milling at 5 g scale is considered sufficient to obtain the target Dv 90 value around 5 pm and a span value below 3. A short stress study was performed to determine which composition might be suitable for in-vivo evaluation.

[0265] Second NS screening - Bead milling part 2

[0266] In a follow-up bead milling screening, it was evaluated whether particle size distribution changes significantly when milled at least twice the time after particle aggregation (i.e. between 8 and 20 h) for three compositions (#12, #14, #16). The three compositions were newly generated, so batch 1 was used in Bead milling part 1 , and batch 2 was used in Bead milling part 2.

[0267] To assess the milling efficiency of the different compositions, particle size was measured after 8, 20, 24, 27, 30 and 46 hours milling using laser diffraction to obtain information on the evolution of the particle size distribution. The results are tabulated in Table 28. Table 28 - PSD as a function of time for the 50 mg / g clozapine compositions

[0268] 1First measurement of five reported

[0269] 2Average value of five reported

[0270] 3Overnight storage

[0271] Up to 8h milling a broad particle size distribution was measured containing very small particles (< 0.2 pm). Presence of very small and very large particles might induce instability in the formulation which is highlighted during laser diffraction measurement. The particle size of compositions remained quite stable upon overnight storage at 2-8°C after 24h milling. After 20h milling, aggregation (i.e. overmilling) was observed for all compositions and a bi-modal distribution was obtained of which the main peak was situated between 1 and 10 pm. The target Dv 90 value around 5 pm and a span value below 3 was reached for all compositions.

[0272] Based on this single experiment, an indication concerning variation in particle size upon increasing the milling time beyond the point of aggregation (in this case between 20h and 46h milling) can be given. The particle size when formulated at 50 mg / g P338 (composition #14) seems most prone to variation in comparison to the composition formulated at 30 mg / g P338 (composition #12). A similar variation in particle size was seen when formulating at pH 8 (composition #12) or at pH 7.5 (composition #16). Overall the PSD was observed to be more stable from 20h milling onward compared to the PSD observed at earlier milling times.

[0273] Similar observations were made during visual evaluation of the compositions at each milling time interval. A change from a yellow suspension to an off-white suspension also occurs between 8h and 20h milling and no yellow particles were seen from 20h milling onwards. However, the suspensions were only observed to be completely off-white after 24h milling compared to 20h during the previous bead milling screening, which indicates some variation between repetitions. Concerning phase separation after overnight storage at 2-8°C, no inhomogeneity was seen.

[0274] Based on these results, the robustness of the milling process at 5 g scale is considered sufficient to increase the milling time above 20h milling if needed for future productions.

[0275] Second NS screening - Evaluation of PSD

[0276] During the second NS screening, three 50 mg / g Clozapine compositions (all containing 50 mg / g Mannitol) were prepared in duplicate, i.e. composition #12, #14 and #16. Based on the results of these two replicates from two batches, information concerning the robustness (and repeatability) of the milling process and influence of storage at 2-8°C was gathered.

[0277] Robustness of the milling process:

[0278] A similar trend concerning the particle size reduction / aggregation was seen in both bead milling experiments performed during the second NS screening. A shift of the PSD to the nanorange was seen up to 8h milling resulting in broad distributions. A shift to the microrange, resulting in a bi-modal distribution, was reached after 20h milling.

[0279] Robustness after 20h milling was only evaluated during the second part of this bead milling study and indicated a fairly stable distribution once aggregation (i.e. from 20h milling onwards) occurred for all compositions. Overlays of the PSD at the different milling time intervals are given in Fig. 2 and Fig. 3.

[0280] Intermediate storage at 2-8C:

[0281] Due to the short milling intervals evaluated during the second NS screening, overnight storage at 2-8°C was implemented in the process. Fig. 4 illustrates the impact of the storage on the particle size distribution after 4h and 24h milling of the three compositions which were prepared in duplicate. Particle size remained quite stable when stored overnight at 2-8°C. Most variation was seen after 4h milling indicating a lower stability compared to samples stored overnight after 24h milling.

[0282] Repeatability

[0283] Repeatability of the milling process at 5 g scale was evaluated at two milling time intervals i.e. 8h (broad PSD) and 20h (bi-modal distribution with main peak between 1 and 10 pm). The same stabilizer solution batch and same Clozapine lot were used to manufacture the compositions. Preparation and milling was performed at different days. Overlays at the different milling time intervals for the three repeated compositions are given in Fig. 5. Most variation in particle size was seen between the replicates after 8h milling. After 20h milling, a similar PSD between replicates was measured for all three compositions.

[0284] Conclusion

[0285] A first screening via bead milling was performed, evaluating several stabilizers ( i.e. DOSS, P188, P338 and Kollidon 30) at different concentrations; a pH between 7 and 8; a molarity of 5 or 10 mM; and the incorporation of a tonicifier. Compositions were milled up to 32h, harvested and subsequently analysed. None of the compositions reached a Dv 90 below 2 pm. pH remained stable for all compositions containing 20 mg / g Kolliphor P338 both at pH 8 and pH 7.5 except when combined with DOSS at pH 7. Compositions containing only Kolliphor P188 indicated an insufficient buffer capacity to stabilize the clozapine particles after milling. The compositions containing 20 mg / g Kolliphor P338, except when combined with DOSS, displayed acceptable assay values ranging between 90 and 110%. Assays below 90% were measured for all other compositions i.e. those with DOSS or with Kolliphor P188, indicating possible homogeneity issues.

[0286] Next, two compositions containing Kolliphor P338 and buffered at pH 8 with or without Mannitol were evaluated via bead milling during a test run. LD measurements at short milling time intervals showed that initially a broad PSD was reached including very small nanoparticles. However, upon further milling agglomeration occurred which resulted in a bi-modal distribution leading to a Dv 90 around 5 pm.

[0287] Based on the results obtained during the first screening and test run, Kolliphor P338 was found to have the best stabilizing properties. Therefore, this surfactant was evaluated at several concentrations i.e. 30, 40 and 50 mg / g buffered at both pH 7.5 and pH 8 during a second screening. In addition, the combination with Kolliphor P188 at 2 mg / g was evaluated. Mannitol at 50 mg / g was included for all compositions to adjust the osmolality to an acceptable value for IM injection. Eight compositions were milled upto 20h, after which off-white homogeneous suspensions were obtained. A bi-modal distribution yielding a Dv 90 value around 5 pm and a stable pH was reached for all compositions. No impurity or degradant peaks were detected above reporting threshold (i.e. 0.05%) and acceptable assay values ranging between 90 and 110% were obtained for all compositions.

[0288] In addition, three of the eight compositions (#12, #14, #16) were selected to evaluate the milling robustness more extensively i.e. increasing the milling time up to 46h. From 20h milling onward, a fairly stable distribution (once agglomeration occurred i.e. after 20h milling) was obtained for all three compositions. Most variation in particle size between the replicates was seen at the 8h interval. After 20h milling, a similar PSD was measured for all three compositions at the different milling times. During the milling trials, compositions were stored overnight at 2-8°C at different milling times. Particle size remained more or less stable during storage. Most variation in PSD before and after overnight storage was seen after 4h milling compared to 20h milling indicating that the bi-modal distribution with the main peak between 1 and 10 pm was more stable compared to the very broad distribution containing smaller particles in terms of DP stability. Six concepts were selected for evaluation in a short stress study.

[0289] Example 3 - Short stress study of compositions comprising clozapine

[0290] Material & methods

[0291] The products, consumables and instruments used in this study are shown in Table 14-16. The phosphate buffer stock solutions were the same as in Example 2. The pH measurements, laser diffraction measurements were performed as described in Example 2. Ns preparation was done as described in Example 2, but in addition a Voxdale (Antwerp, Belgium) roller mill was used next to a Peira (Beerse, Belgium) roller mill for low shear milling.

[0292] For evaluating the appearance of the suspensions before harvesting, the method according to Example 2 was applied. The following method was applied to evaluate appearance after harvesting: The appearance was evaluated via visual inspection in a liquid viewer Apollo 2 (black and white cabinet). Color, flow behavior, homogeneity, extent of sedimentation and feasibility of resuspending the sediment were evaluated in three steps:

[0293] Step 1 : Observations without moving the container.

[0294] Step 2: Observation of sediment behavior, flow behavior.

[0295] Step 3: Evaluation of effort needed to homogenize the suspension.

[0296] Three different methods could be used to check the required effort to homogenize the sample or resuspend a sediment layer, whereby the force applied to the sample was gradually increased:

[0297] Simple head-over-head tumbling for a maximum of 10 times.

[0298] Shaking: the bottle is turned horizontally and moved moderately for a maximum of 30 seconds. Vigorous shaking: maximum 5 times for 10 seconds.

[0299] It was noted if vigorous shaking was not sufficient to resuspend a sediment layer or homogenize a sample. In case a sample looked homogeneous, tumbling was anyway applied in order to confirm the homogeneity.

[0300] For measuring the osmolality, the same method was used as in Example 2, but now the samples were measured in triplicate of which the average value is reported.

[0301] The Assay / Purity determination was carried out as described in Example 2, with the addition that values below reporting threshold are reported for information only and are not included in the sum of impurities and degradants Q MP / DEG). Moreover, for the assay determination of placebo solutions, single analysis was performed.

[0302] Production

[0303] Table 29 tabulates the compositions prepared forthe short stress study, prepared at 50 mg / g Clozapine. The surfactants / suspending agents and their concentrations were chosen based on the results of Example 2, as was the phosphate buffer at pH 7.5 or 8.0 and the molarity of 5 mM. Mannitol was incorporated as tonicifier. Four compositions represent different batches of compositions used in Example 2, for simplicity the numbers have been kept consistent. There are two new compositions, compositions #17 and #18, both are very similar to composition #11 of Example 1 , but the Kolliphor P338 concentration has been changed from 20 to 30 mg / g. In composition #17 and #18, the pH is set to 7.5 and 8, respectively.

[0304] Table 29 - Compositions evaluated during short stress study 1 .

[0305] 1Clozapine batch A-170577 was used. No CF was applied.

[0306] Eight subbatches per composition were prepared at 5 g scale and milled for 20h, at which time the appearance and PSD (particle size distribution) was checked. If the compositions were not acceptable regarding appearance (i.e. suspension has a yellow color or yellow particles are visible) or PSD, the compositions were further milled up until 23h milling, 37h milling or 40h milling. In case the PSD or appearance was not acceptable at the last milling time point (i.e. 37h or 40h milling), it was discarded or harvested separately to investigate the influence of the less favorable PSD or appearance on stability.

[0307] In terms of appearance, both colour and presence of yellow particles were assessed:

[0308] • In case the suspension was white to off-white, the suspension was considered as acceptable to harvest and pool.

[0309] • In case the suspension had a yellow aspect or displayed a pronounced presence of yellow particles at the final milling time point, i.e. 37h or 40h, the suspension was considered less favorable. The decision to discard or harvest without pooling was made taking into account the PSD result.

[0310] The second evaluated factor was PSD. Based on the Example 2 a bi-modal distribution with a Dv 90 around 5 pm and a span value below 3 was targeted.

[0311] An overview of the appearance and PSD results of the subbatches before harvesting (i.e. at the last milling timepoint) is given in Table 30. All off-white suspensions were harvested and analysed. Subbatch #12.1 and 17.3 were harvested, but not included in the final DP pool due to the yellow aspect and in the latter presence of yellow particles at the final milling time point. These subbatches were analysed at TO and after 4 weeks storage at 25°C / 60%RH and 40°C / 75%RH for appearance and assay / purity.

[0312] Furthermore, although subbatch #14.7 and #15.7 contained few yellow particles at the final milling time point, an acceptable PSD was measured. The few yellow particles present were considered neglectable in this case. Hence the subbatches were included in the final DP pool. All subbatches of the composition containing 5 mg / g Kollidon 30, buffered at pH 8, i.e. #17.8, contained yellow particles at the final milling time point. However, as an acceptable PSD was measured, subbatches were harvested and pooled. The inventors found that a longer milling time can be required to avoid yellow particles when Kollidon 30 is present. Subbatch #16.8 displayed yellow particles and some phase separation at the final milling time point. A slightly higher Dv 90 was measured, but span value was acceptable. As already two subbatches of this composition were considered unacceptable it was decided to include subbatch #16.8 in the final DP pool despite of the less favorable appearance and particle size. Table 30 - Overview appearance and PSD results of the 50 mg / g clozapine subbatches before harvesting at last milling time point

[0313] (1)First LD measurement of five reported (variability > acceptable % between consecutive measurements and trend observed over subsequent measurements; <2> Average LD value of five reported; <3> Not included in DP pool; NM: not measured due to complete phase separation Table 31 displays which subbatches were pooled for each final DP formulation and lists the harvested amount available for the short stress study. Table 31 - Harvested amount of pooled suspensions

[0314] For the vial filling, it was foreseen to fill 3 mL in a clear 4R vial for all analysis concerning physical stability (i.e. appearance, pH, PSD and osmolality) per condition and time point. For the chemical analysis (i.e. A / P), it was foreseen to fill 1 mL in a clear 2R vial per condition and time point. The vials were closed with 13 mm bromobutyl stoppers and capped with a 13 mm aluminum crimp seal.

[0315] In addition to the DP’s, placebo solutions were prepared as a reference point regarding assay / purity analysis. The composition and manufacturing procedure was similar to that of the stabilizer solutions, with the difference that no overage of excipient or buffer concentration is taken into account. Hence the concentration of stabilizers is identical to that of the final compositions. An equal number of vials (3 mL in a clear 4R vial and 1 mL in a clear 2R vial) were filled for each placebo batch as was foreseen for the DPs.

[0316] Results - Appearance (1 / 5)

[0317] In terms of appearance, inhomogeneity was observed from 2 weeks storage for all compositions at all evaluated storage conditions, which was more pronounced at higher storage temperature. After 4 weeks at 2-8°C and 25°C / 60%RH, (vigorous) shaking was required to resuspend the sediment. Suspensions were off-white at all conditions, except at 60°C. After 2 weeks at 60°C, all suspensions had yellow sediment, except composition #17 which had off-white sediment. Yellow crystals were observed in all compositions except for composition #16. After 4 weeks at 40°C / 75%RH, all suspensions displayed sedimentation. Vigorous shaking was applied to resuspend the sticky sediment.

[0318] Results - Osmolality (2 / 5)

[0319] The osmolality remained stable over 4 weeks storage both at 25°C / 60%RH and 2-8°C, see Table 32. Table 32 - Results in terms of osmolality in the short stress study

[0320] (1)Average of three measurements Results - pH (3 / 5)

[0321] The pH increased slightly over 4 weeks storage at 2-8°C and 25°C / 60%RH, except for composition #18 in which a pH decrease was observed after 4 weeks at 25°C / 60%RH. The pH increase was most pronounced when stored at 25°C / 60%RH. Least pH variation was observed in compositions #17 and #16. Results are shown in Table 33. Table 33 - Results in terms of pH in short stress study

[0322] Results - Chemical stability (4 / 5)

[0323] Furthermore, assay and purity profile was in line with TO after 4 weeks storage at both 25°C / 60%RH and 40°C / 75%RH for all compositions. No impurities / degradants were detected above reporting threshold. After 2 weeks storage at 60°C, low assays for clozapine (< 30%) were measured for Ns compositions #12, #14, #15 and #18, whereas assay of clozapine was in line with TO for Ns composition #17. Only at 60°C, impurities / degradants were detected but below reporting threshold (i.e. RRT 1 .67 in all Ns compositions and RRT 1.15 #17).

[0324] Table 34 - Results in terms of assay / purity in short stress study

[0325] (^Vigorous shaking (2 min) was needed to resuspend sedimentation isually large particles were seen after homogenization which sedimented quickly during sample preparation

[0326] Results - Laser diffraction (5 / 5)

[0327] In view of laser diffraction, the Mannitol / P338 compositions were more stabilized when stored at 2-8°C. The higher Kolliphor P338 concentration (i.e. 50 mg / g) seemed to result in less variation in particle size over time compared to the same composition at 30 mg / g. The addition of Kolliphor P188 improved the stabilization of the particle size and the composition was most stable when stored at 2-8°C. Over time, the composition with Kollidon 30 at pH 7.5 seemed to have less variation compared to TO than the composition with Kollidon®30 at pH 8.0. Table 35 - Laser diffraction results of the short stress study

[0328] Average of five measurements reported unless mentioned otherwise

[0329] (1)First measurement of five reported (variability > 10% (Dv 10 & Dv90) and > 6% (Dv50) between consecutive measurements and trend observed over subsequent measurements)

Claims

Claims1 . Composition comprising a piperazine-benzazepine, a buffer, and a surfactant, wherein the buffer is a phosphate buffer; and the surfactant is a non-ionic block copolymer surfactant.

2. The composition according to claim 1 , wherein the buffer has a pH of 6.5-8.5, preferably of 7-8.

3. The composition according to claim 1 or 2, wherein the buffer is a 1 -30 mM phosphate buffer, preferably 2-25 mM, more preferably 3-20 mM, most preferably 4-15 mM.

4. The composition according to any one of claims 1 -3, wherein the composition comprises at least 2.5 wt.-% surfactant.

5. The composition according to any one of claims 1-4, wherein the block copolymer comprises a hydrophobic block flanked by two hydrophilic blocks.

6. The composition according to any one of claims 1-5, wherein the composition comprises 1- 15 wt.-% piperazine-benzazepine, preferably 2.5-10 wt.-%, such as 5 wt.-%, wherein the piperazine-benzazepine is preferably clozapine.

7. The composition according to any one of claims 1-6, wherein the composition is a nanoparticle suspension.

8. The composition according to claim 7, wherein 90% of the particles have a particle size smaller than 10 pm, preferably between 0.1-5 pm, such as about 2.5 pm; or wherein the particles have a particle size distribution with a span less than 5, preferably between 1 -4, more preferably between 1.5-3.5, most preferably between 2-3, and wherein the particle size or particle size distribution is determined by laser diffraction.

9. The composition according to any one of claims 1-8, wherein the composition is stable during storage for at least 2 weeks, preferably for at least about 4 weeks, wherein storage conditions are preferably at 2-8°C or at 25°C with a relative humidity of about 60%.

10. The composition according to any one of claims 1-9, wherein the composition further comprises a tonicifier, such as a carbohydrate, a sugar alcohol, or a hydrophylic polymer, preferably the composition comprises 1-10 wt.-% tonicifier, more preferably 2.5-7.5 wt.-%, most preferably around 5 wt.-%.

11. The composition according to any one of claims 1-10, wherein the composition further comprises a suspending agent such as polyvinylpyrrolidone, preferably between 0.1 -5 wt.- % suspending agent, more preferably 0.2-4 wt.-%, still more preferably 0.3-3 wt.-%, still more preferably 0.4-2 wt.-%, most preferably around 0.5 wt.-%, wherein the pH of the composition is preferably about 7-8 such as 7.5.

12. The composition according to any one of claims 1 -11 , wherein the osmolality of the composition is below 600 mOsm / kg, preferably between 250-500 mOsm / kg, more preferably between 350-450 mOsm / kg, and wherein the osmolality is determined at room temperature.

13. The composition according to any one of claims 1-12, wherein the composition has a pH of about 7.5-8, and / or the buffer is a 4-6 mM phosphate buffer, and / or the composition comprises about 2.5-5.5 wt.-% surfactant, and / or the composition comprises about 4-6 wt.-% clozapine, and / or the composition comprises about 4-6 wt.-% sugar alcohol, and / / or the composition comprises about 0.4-0.6 wt.-% polyvinylpyrrolidone.

14. The composition according to any one of claims 1 -13, wherein the buffer is a 5 mM phosphate buffer and the composition comprises about 5 wt.-% clozapine and about 5 wt.- % mannitol, wherein the composition further comprises: i) about 3 wt.-% poloxamer 338, wherein the pH of the composition is 8; or ii) about 5 wt.-% poloxamer 338, wherein the pH of the composition is 8; or iii) about 3 wt.-% poloxamer 338 and about 0.2 wt.-% poloxamer 188, wherein the pH of the composition is 8; or iv) about 3 wt.-% poloxamer 338 and about 0.5 wt.-% polyvinylpyrrolidone, wherein the pH of the composition is 8; or v) about 3 wt.-% poloxamer 338, wherein the pH of the composition is 7.5; or vi) about 3 wt.-% poloxamer 338 and about 0.5 wt.-% polyvinylpyrrolidone, wherein the pH of the composition is 7.5.

15. Method for treating, preventing, and / or suppressing symptoms of schizophrenia, schizoaffective disorders, and / or Parkinson's disease, wherein the method comprising the step of administering to a subject a composition according to any one of claims 1-14.

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