Tranexamic acid compositions

Abstract

Disclosed are compositions comprising particles of tranexamic acid, the particles of tranexamic acid having a D90 of 5.0 µm or less, along with methods of making the compositions, uses of the compositions, and devices containing the compositions.

Description

[0001] TRANEXAMIC ACID COMPOSITIONS

[0002] TECHNICAL FIELD

[0003] This invention relates to compositions comprising particles of tranexamic acid. The invention further relates to methods of making the compositions, uses of the compositions, and devices containing the compositions.

[0004] BACKGROUND

[0005] Tranexamic acid was invented in the early 1960's by Shosuke and Utako Okamoto who reported the invention of l-(amino methyl)-cyclohexane-4-carboxylic acid (AMCHA), now known as tranexamic acid (Brenner). Tranexamic acid is a synthetic analogue of the amino acid lysine that blocks the conversion of plasminogen to plasmin and inhibits binding of plasmin to fibrin which stabilises the fibrin matrix and thus reduces bleeding. (O'Neil).

[0006] US Patent 3950405 discloses trans-4-(aminomethyl)cyclohexane carboxylic acid with the generic name of tranexamic acid. Tranexamic acid may be prepared, for example, as described in US 39505405, from trans-4-cyanocyclohexane-carboxylic acid or its lower alkyl esters by hydrogenation at high pressure and temperature. Improved methods of producing tranexamic acid have been identified, such as that described in WO 2015 / 104721.

[0007] Acute trauma is a common cause of death across all age groups associated with a high risk of mortality and time is of essence with regards to treating patients with lifethreatening bleeding. The landmark CRASH-2 (Clinical Randomisation of Anti-fibrinolytic in Significant Haemorrhage) clinical trial initiated in 2005 showed that tranexamic acid significantly reduced death due to bleeding and all-cause mortality, with no increase in vascular occlusive events. The reduction in death was greatest when tranexamic acid was given within 3 hours of injury. When tranexamic acid was given after 3 hours there was no mortality benefit. On the results of the CRASH-2 trial, tranexamic acid was included on the World Health Organisation (WHO) List of Essential Medicines and was also incorporated into trauma protocols in many countries around the world (Brenner et al.). The CRASH-2 trial confirmed the efficacy of tranexamic acid in acute traumatic haemorrhage, demonstrating a one-third reduction in mortality when given within three hours of the inciting event. (Cai et al. 2020, Brenner et al., 2019). Whilst the CRASH-2 study was underway the landmark WOMAN (World Maternal Anti-fibrinolytic) trial was launched in 2009. The WOMAN study showed a survival benefit to the use of tranexamic acid in patients with postpartum haemorrhage with no increase in thromboembolic events (Brenner et al., 2019). The World Health Organisation (WHO) recommends that tranexamic acid is used for post-partum haemorrhage as a first line treatment (Vogel et al., 2018). In a clinical setting, the use of the injection product provides a rapid systemic therapeutic blood level of tranexamic acid. The oral tablet dosage form only achieves therapeutically effective blood levels (lOmg / L) and maximum levels after >1 hour and 2-4 hours respectively (Grassin-Delyle et al, 2022) and so is not suitable for rapid, emergency treatment.

[0008] Urgent treatment of post-partum haemorrhage is required since women with postpartum haemorrhage die quickly due to haemorrhage bleeding and tranexamic acid, the WHO recommended drug, is most effective when given early (Vogel at al 2018). In clinical situations, intravenous injections of tranexamic acid (such as Celtranz™) can be administered. However alternative routes of administration are required to deal with the large numbers of non-clinical based emergencies, providing increased accessibility and reduced time for treatment (Vogel et al, 2018).

[0009] Alternative forms of tranexamic acid that can provide rapid onset of action and are suitable for use outside of clinical settings would therefore be desirable.

[0010] SUMMARY OF THE INVENTION

[0011] In a first aspect, the invention provides a composition comprising particles of tranexamic acid, the particles of tranexamic acid having a D90of 5 pm or less.

[0012] In a second aspect, the invention provides a composition comprising particles of tranexamic acid as hereinbefore described, wherein the particles of tranexamic acid are obtained by supercritical anti-solvent (SAS) precipitation.

[0013] In a third aspect, the invention provides a method of preparing a composition comprising particles of tranexamic acid, the method comprising contacting a fluid anti-solvent with a solution comprising tranexamic acid in a solvent, to precipitate said particles of tranexamic acid.

[0014] In a fourth aspect, the invention provides a composition comprising particles of tranexamic acid obtained by a method according to the third aspect.

[0015] In a fifth aspect, the invention provides a pharmaceutical composition comprising (or consisting of) a therapeutically effective amount of a composition comprising particles of tranexamic acid according to any of the first, second and fourth aspects.

[0016] In a sixth aspect, the invention provides the composition according to any of the first, second, fourth and fifth aspects for use as a medicament. In a seventh aspect, the invention provides the composition according to any of the first, second, fourth and fifth aspects for use in the prevention or treatment of blood loss.

[0017] In an eighth aspect, the invention provides the composition according to any of the first, second, fourth and fifth aspects for use in the prevention or treatment of a disorder selected from the group consisting of: haemorrhage, trauma, uterine bleeding and bleeding disorders.

[0018] In a ninth aspect, the invention provides a method of treating a disorder in a patient, the method comprising administering to said patient a therapeutically effective amount of the composition according to any of the first, second, fourth and fifth aspects.

[0019] In a tenth aspect, the invention provides the composition according to any of the first, second, fourth and fifth aspects in an amount of at least 50 mg.

[0020] In an eleventh aspect, the invention provides an inhalation or insufflation device having therein the composition according to any of the first, second, fourth and fifth aspects.

[0021] BRIEF DESCRIPTION OF THE DRAWINGS

[0022] One or more embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings, in which :

[0023] Figure 1 is a SEM of as supplied tranexamic acid

[0024] Figure 2 is a SEM of tranexamic acid formed by conventional solvent evaporation crystallisation from methanol :acetic (9: 1 v / v) solution

[0025] Figure 3 is a SEM of tranexamic acid (as supplied) particles following milling

[0026] Figure 4 is particle size analysis of milled tranexamic acid particles

[0027] Figure 5 is an SEM of tranexamic acid precipitated in Example 5

[0028] Figure 6 is an SEM of tranexamic acid precipitated in Example 6

[0029] Figure 7 is an SEM of tranexamic acid precipitated in Example 7

[0030] Figure 8 is an SEM of tranexamic acid precipitated in Example 8

[0031] Figure 9 is an SEM of tranexamic acid precipitated in Example 9

[0032] Figure 10 is an SEM of tranexamic acid precipitated in Example 10

[0033] Figure 11 is an SEM of tranexamic acid precipitated in Example 11 Figure 12 is an SEM of tranexamic acid precipitated in Example 12

[0034] Figure 13 is an SEM of tranexamic acid precipitated in Example 13

[0035] Figure 14 is an SEM of tranexamic acid precipitated in Example 14

[0036] Figure 15 is an SEM of tranexamic acid precipitated in Example 15

[0037] Figure 16 is an SEM of tranexamic acid precipitated in Example 16

[0038] Figure 17 is an SEM of tranexamic acid precipitated in Example 17

[0039] Figure 18 is an SEM of tranexamic acid precipitated in Example 18

[0040] Figure 19 is an SEM of tranexamic acid precipitated in Example 19

[0041] Figure 20 is an SEM of tranexamic acid precipitated in Example 20

[0042] Figure 21 is an SEM of tranexamic acid precipitated in Example 21

[0043] Figure 22 is an SEM of tranexamic acid precipitated in Example 22

[0044] Figure 23 is an SEM of tranexamic acid precipitated in Example 23

[0045] Figure 24 is an SEM of a 5 g batch of tranexamic acid precipitated in Example 24

[0046] Figure 25 is an SEM of a 10 g batch tranexamic acid precipitated in in Example 25

[0047] Figure 26 is an SEM of a 15 g batch tranexamic acid precipitated in Example 26

[0048] Figure 27 shows the particle size analysis for tranexamic acid precipitated in Example 21 at 2 bar aerosolisation pressure

[0049] Figure 28 shows SEM analysis of Example 21 after 5 years ambient storage

[0050] Figure 29 shows particle size analysis of example 21 after 5 years of ambient storage at 2 bar aerosolisation pressure

[0051] Figures 30A and 30B are respectively HPLC traces for tranexamic acid (as supplied starting material, Sigma Aldrich, 97% purity) and tranexamic acid precipitated in Example 21

[0052] Figure 31 is Next Generation Impactor data for Example 21 Figure 32 are representative SEMs of tranexamic acid precipitated in Examples 25 and 26, respectively

[0053] Figure 33 are two representative PXRD profiles of tranexamic acid precipitated in Examples 25 and 26, respectively

[0054] Figure 34 is the PXRD profile of the as supplied tranexamic material

[0055] Figure 35A shows SEM, Figure 35B shows the particle size distribution at 2 bar aerosolization pressure and Figure 35C the PXRD profile of the powder blend of Examples 23 and 24 which were used in the bioavailability study.

[0056] Figure 36 shows pharmacokinetic data for Control Group (tranexamic acid administered intragastrically 60 mg / kg dose, in aqueous solution made from powder blend prepared from powders produced in Examples 23 and 24)

[0057] Figure 37 shows pharmacokinetic data for Test Group (tranexamic acid administered by inhalation, 8.62 mg / kg dose, powder blend prepared from powders produced in Examples 23 and 24).

[0058] Figure 38 shows that Example 26 remains physically stable after 5 years ambient storage by SEM analysis

[0059] DETAILED DESCRIPTION

[0060] Disclosed herein are novel forms of tranexamic acid (TXA), methods of making them and uses of them. The inventors have surprisingly found that by employing a modified supercritical antisolvent precipitation process, dry powder forms having desirable morphological properties can be prepared. This was previously unknown.

[0061] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and do not exclude other components, integers or steps. Moreover, the singular encompasses the plural unless the context otherwise requires: in particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0062] Preferred features of each aspect of the invention may be as described in connection with any of the other aspects. Within the scope of this application, it is expressly intended that the various aspects, embodiments, examples and alternatives set out in the preceding paragraphs, in the claims and / or in the following description and drawings, and in particular the individual features thereof, may be taken independently or in any combination. That is, all embodiments and / or features of any embodiment can be combined in any way and / or combination, unless such features are incompatible.

[0063] Where upper and lower limits are quoted for a property, then a range of values defined by a combination of any of the upper limits with any of the lower limits may also be implied.

[0064] In this specification, references to properties are - unless stated otherwise - to properties measured under standard temperature and pressure, i.e., at atmospheric pressure and at a temperature of 20°C.

[0065] All particle sizes (diameters) herein are volume-based particle diameters, measured for example by laser diffraction, and relate to the maximum particle diameter.

[0066] For acicular particles, average particle lengths can be determined from analysis of scanning electron microscopy (SEM) images. Aspect ratios may also be determined from analysis of SEM images.

[0067] Further details on the techniques used to determine the properties and characteristics of the invention are provided in the examples section.

[0068] In a first aspect, the invention provides a composition comprising particles of tranexamic acid, the particles of tranexamic acid having a D90of 5.0 pm or less. The composition is preferably a dry powder composition. The particles of tranexamic acid are preferably obtainable by supercritical anti-solvent (SAS) precipitation.

[0069] The composition according to the first aspect surprisingly exhibits an advantageous combination of properties that make it an ideal candidate for drug formulation, particularly for administration by inhalation. These include desirable morphology and particle size characteristics (small particle size, narrow monomodal particle size distribution, low aspect ratio), and are present in the as formed material obtained directly from the supercritical antisolvent precipitation process, with no further processing (such as milling, etc.) required. The composition also exhibits high crystalline purity and good stability. The composition according to the first aspect may preferably consist of the particles (e.g. crystalline particles) of tranexamic acid.

[0070] Whilst there are several examples of administration of tranexamic acid by the respiratory tract these have been exclusively aimed at local treatment of lung disorders, primarily lung bleeding in children (O'Neil et al, 2020) and for haemoptysis (Haghi et al, 2015) and the forms of tranexamic acid used are not suitable to achieve the effective deposition in the deep lung compartments that is needed for effective systemic delivery. Administration of tranexamic acid via the lungs for rapid systemic uptake provides the basis for a wider available drug delivery system for non-clinic locations and selfadministration by patients, for example women suffering from post-partum haemorrhage.

[0071] When considering the preparation of inhalable or insufflable powder formulations containing an antifibrinolytic agent, in particular tranexamic acid, there are a number of challenges to be overcome. The particles of the drug substance need to be prepared with a suitable particle size typically 1 - 10 microns, morphology and topography which aerosolise readily on administration from a suitable powder inhaler device. Conventional crystallisation / precipitation from organic solvent solutions often generates particles with irregular shaped crystals with broad particle size distributions and some particles over 100 microns in size, as found for tranexamic acid and illustrated in Figure 1. Such material is unsuitable for effective and efficient drug deposition in the deep alveolar regions of the lungs, the target deposition zone for enabling rapid absorption across the large mucosal surface area and consequential systemic drug delivery.

[0072] Other conventional approaches to prepare suitable powder formulations are to mill / micronise larger crystals of material. Whilst this approach can generate particles in respirable ranges, the milled products are generally highly charged and cohesive leading to difficulties in secondary processing operations, such as powder flow and mixing (Hoppentocht et al, 2014). Amorphous domains of different content between batches of material tend to form on milling which can result in moisture sensitivity and particle growth following moisture uptake. As a random event, particle breakage and fracture on milling produces uncontrolled particle sizes and particle morphology. Such events can result in broad and multimodal size distributions, tending to cause agglomeration and coherence of small particles with high surface energetics on the surfaces of larger particles. In addition particle exhibit irregular ill-defined particle shapes. These particle assemblies do not aerosolise and fluidise easily.

[0073] The composition according to the first aspect has an advantageous morphology and particle shape / size for administration by inhalation / insufflation. Preferably, in the composition according to the first aspect the particles of tranexamic acid have a Di0of 2.0 pm or less, preferably 1.5 pm or less, more preferably 1.0 pm or less, e.g., 0.8 pm or less, or 0.7 pm or less. The particles of tranexamic acid preferably have a Di0of from 0.1 pm to 2.0 pm, more preferably from 0.2 pm to 1.5 pm, still more preferably from 0.4 pm to 1.0 pm, e.g., from 0.5 pm to 0.8 pm. Preferably, in the composition according to the first aspect the particles of tranexamic acid have a D50of 4.0 pm or less, preferably 3.0 pm or less, more preferably 2.5 pm or less, e.g., 2.0 pm or less. The particles of tranexamic acid preferably have a D50of from 0.5 pm to 4.0 pm, more preferably from 1.0 pm to 3.0 pm, still more preferably from 1.5 pm to 2.5 pm, e.g., from 1.5 pm to 2.0 pm.

[0074] In the composition according to the first aspect, the particles of tranexamic acid have a D90of 5.0 pm or less, preferably 4.5 pm or less, more preferably 4.0 pm or less, e.g. 3.5 pm or less. The particles of tranexamic acid preferably have a D90of from 1.0 pm to 5.0 pm, more preferably from 2.0 pm to 5.0 pm, still more preferably from 2.5 pm to 4.5 pm, e.g. from 3.0 pm to 4.0 pm.

[0075] A small particle size, along with a narrow particle size distribution, aids aerosolisation, and therefore is advantageous for deep lung delivery by inhalation / insufflation. Efficient delivery to the deep lung is particularly important for effective systemic (rather than local) treatment.

[0076] Preferably, the particles of tranexamic acid have a monomodal particle size distribution.

[0077] Preferably, in the composition according to the first aspect, the particles of tranexamic acid have a volume mean diameter of 4.0 pm or less, preferably 3.0 pm or less, more preferably 2.5 pm or less, e.g., 2.0 pm or less. The particles of tranexamic acid preferably have a volume mean diameter of from 0.5 pm to 4.0 pm, more preferably from 1.0 pm to 3.0 pm, still more preferably from 1.5 pm to 2.5 pm, e.g., from 1.5 pm to 2.0 pm.

[0078] Preferably, in the composition according to the first aspect, the particles of tranexamic acid have an aspect ratio (e.g., an average aspect ratio) of from 1 : 1 to 5: 1, more preferably from 1 : 1 to 4: 1, still more preferably from 1: 1 to 3: 1. A lower aspect ratio advantageously means that particles have a similar length and width. This provides a preferred shape for drug delivery to the lung by inhalation / insufflation. High aspect ratios (e.g., of greater than 1:5) are associated with long acicular, needle-like particles which are not suitable for pulmonary administration.

[0079] In a preferred composition of the first aspect, less than 10 vol% of the particles of tranexamic acid have a particle size of greater than 6 pm. More preferably, less than 8 vol% of the particles of tranexamic acid have a particle size of greater than 6 pm. Still more preferably, less than 5 vol%, or less than 2 vol% (e.g. less than 1 vol%), of the particles of tranexamic acid have a particle size of greater than 6 pm. Preferably, the composition of the first aspect is substantially devoid of tranexamic acid particles having a particle size of greater than 6 pm. Having a minimal proportion of particles of 6 pm or greater is advantageous because particles of 6 pm or greater do not reach the deep lung compartments. They are therefore not effective for systemic drug delivery via pulmonary mechanisms such as inhalation.

[0080] The composition according to the first aspect is preferably a dry powder composition. In the composition according to the first aspect, the particles of tranexamic acid are preferably in crystalline form. The particles of tranexamic acid are preferably substantially free of amorphous material. The presence of amorphous material is disadvantageous because amorphous domains tend to be hygroscopic, leading to water- induced bridging and particle growth over time. In the composition according to the first aspect, the particles of tranexamic acid preferably contain less than 10% by weight, more preferably less than 5% by weight, still more preferably less than 1% by weight amorphous material. Preferably, the particles of tranexamic acid are in a substantially pure crystalline form, e.g., having at least 90%, preferably at least 95%, more preferably at least 98%, still more preferably at least 99% crystallinity.

[0081] Purity / crysta II in ity may, for example, be determined using powder x-ray diffraction, IR / Raman spectroscopy or HPLC.

[0082] Preferably, in the composition according to the first aspect, the particles of tranexamic acid have a monomodal particle size distribution. Beneficially this provides a uniform powder formulation with advantageous morphology for pulmonary administration.

[0083] In the composition according to the first aspect, the particles of tranexamic acid are advantageously produced directly with the desirable morphology and particle characteristics described above, from a supercritical antisolvent precipitation process. No additional processing, such as milling or micronisation, is required to achieve the desired particle size and morphology characteristics. The particles of tranexamic acid in the composition according to the first aspect is thus preferably not micronized or milled. The composition according to the first aspect is preferably not spray-dried. Processes such as milling, micronisation and spray drying, particularly when applied to tranexamic acid, tend to produce particles with undesirable characteristics for administration by inhalation, including broad particle size distributions, multimodal (e.g. bimodal) particle size distributions, charged surfaces leading to cohesion of smaller particles to larger ones, and inter-particle agglomeration. These characteristics significantly impede the delivery of the drug to the deep lung compartments, and are therefore ineffective for administration by inhalation, particularly where systemic treatment is desired. The inventors have found that the composition according to the first aspect, once formed, is surprisingly stable under ambient conditions, with no significant changes in particle size characteristics or morphology. This advantageously makes the composition according to the first aspect well suited for use in pharmaceutical applications, where stability and consistency are key. Storage stability may be assessed by determining changes in the composition (e.g., by HPLC) and / or particle size characteristics (Di0, D50, D90, VMD) over time.

[0084] The composition according to the first aspect preferably exhibits no chemical degradation, as measured by HPLC, after 6 months, preferably 12 months, more preferably 24 months, still more preferably 48 months, at ambient conditions or at 40 °C and 75% relative humidity.

[0085] The Dio of the particles of tranexamic acid preferably changes by no more than 25%, preferably no more than 20%, more preferably no more than 15%, still more preferably no more than 10% after 6 months, preferably 12 months, more preferably 24 months, still more preferably 48 months, at ambient conditions or at 40 °C and 75% relative humidity.

[0086] The D50of the particles of tranexamic acid preferably changes by no more than 30%, preferably no more than 25%, more preferably no more than 20%, still more preferably no more than 10% after 6 months, preferably 12 months, more preferably 24 months, still more preferably 48 months, at ambient conditions or at 40 °C and 75% relative humidity.

[0087] The D90of the particles of tranexamic acid preferably changes by no more than 30%, preferably no more than 25%, more preferably no more than 20%, still more preferably no more than 10% after 6 months, preferably 12 months, more preferably 24 months, still more preferably 48 months, at ambient conditions or at 40 °C and 75% relative humidity.

[0088] The volume mean diameter of the particles of tranexamic acid preferably changes by no more preferably changes by no more than 30%, preferably no more than 25%, more preferably no more than 20%, still more preferably no more than 10% after 6 months, preferably 12 months, more preferably 24 months, still more preferably 48 months, at ambient conditions or at 40 °C and 75% relative humidity.

[0089] The aspect ratio of the particles of tranexamic acid preferably changes by no more than preferably changes by no more than 30%, preferably no more than 25%, more preferably no more than 20%, still more preferably no more than 10% after 6 months, preferably 12 months, more preferably 24 months, still more preferably 48 months, at ambient conditions or at 40 °C and 75% relative humidity.

[0090] The composition according to the first aspect advantageously has optimum morphology and particle size characteristics for pulmonary delivery, enabling effective tranexamic acid drug deposition in the deep lung compartments, allowing for systemic delivery and treatment via inhalation for the first time. The fine particle fraction (FPF) generated during the patient inhalation reaches the lungs and gives the necessary therapeutic action either locally, or through absorption into the bloodstream for systemic delivery. To develop a stable dry powder inhalation product with the consistent delivery of fine particle fraction for the product shelf life is a challenge.

[0091] The composition according to the first aspect (or the tranexamic acid particles of the composition) preferably exhibits a fine particle fraction of at least 65%, more preferably at least 70%, still more preferably at least 75%. The fine particle fraction can be determined by various techniques including glass twin impinger (GTI), Anderson Cascade Impactor (ACI) and next generation impactor (NGI). Preferably the fine particle fraction is determined by next generation impactor (NGI), for example at a flow rate of 100 litres per minute. The high fine particle fraction provided by the compositions of the present invention advantageously mean that a therapeutically effective payload for systemic treatment can be delivered via inhalation. This is simply not possible for known tranexamic acid compositions (e.g. those made via spray drying processes).

[0092] The composition according to the first aspect (or the tranexamic acid particles of the composition) preferably exhibits a geometric standard deviation (GSD) of less than 4 pm, preferably less than 3 pm, more preferably less than 2 pm. The GSD can be determined by various techniques including glass twin impinger (GTI), Anderson Cascade Impactor (ACI) and next generation impactor (NGI). Preferably the GSD is determined by next generation impactor (NGI), for example at a flow rate of 100 litres per minute.

[0093] In a second aspect, the invention provides a composition comprising particles of tranexamic acid as hereinbefore described, obtained by supercritical anti-solvent (SAS) precipitation. Preferred features of the supercritical anti-solvent precipitation process are as described below in relation to the third aspect.

[0094] In a third aspect, the invention provides a method of preparing a composition comprising particles of tranexamic acid, the method comprising contacting a fluid anti-solvent with a solution comprising tranexamic acid in a solvent, to precipitate said particles of tranexamic acid. The inventors have surprisingly found that by using an anti-solvent precipitation process, particulate forms of tranexamic acid having desirable properties may be prepared. Advantageously, the process allows for the preparation of tranexamic acid compositions having beneficial morphology and high stability. The specific morphology achieved by the process allows effective pulmonary delivery to the deep lung compartments, allowing for the first time the administration of tranexamic acid by inhalation / insufflation for systemic treatment of various conditions. Advantageously, the inventors have developed a specific process and conditions that enable this to be achieved. Thus preferably, the method comprises contacting the fluid anti-solvent and the solution comprising tranexamic acid in a solvent under such conditions to precipitate said composition comprising particles of tranexamic acid having properties as hereinbefore described with respect to the first aspect of the invention.

[0095] The starting tranexamic acid material used in the method according to the third aspect (i.e., the tranexamic acid used to form the solution) may be an amorphous form of tranexamic acid, a crystalline form of tranexamic acid or a mixture thereof. The method of the third aspect provides a reliable, reproducible method of preparing an inhalable composition of particles of tranexamic acid having the desired morphological properties, regardless of the nature of the tranexamic acid starting material. Conversion of amorphous material to crystalline material, and / or the transformation of crystalline material having undesirable morphology into a readily inhalable formulation can be achieved. The method of the third aspect may therefore further comprise dissolving tranexamic acid starting material in the solvent to form a solution comprising tranexamic acid in a solvent, prior to contacting a fluid anti-solvent with the solution comprising tranexamic acid in the solvent. The tranexamic acid starting material (i.e. prior to dissolution in the solvent) may in some embodiments possess one or more of the following properties: broad particle size distribution. amorphous domains.

[0096] - comprises particles with particle size (largest dimension) of greater than 20 pm, greater than 50 pm or greater than 100 pm.

[0097] D50of greater than 20 pm, greater than 50 pm or greater than 100 pm.

[0098] D90of greater than 50 pm, greater than 100 pm or greater than 250 pm.

[0099] VMD of greater than 20 pm, greater than 50 pm or greater than 100 pm. irregular morphology.

[0100] - agglomeration.

[0101] In the method according to the third aspect, the fluid anti-solvent may preferably be in the form of a stream. Contacting the fluid anti-solvent with the solution of the compound of tranexamic acid in a solvent may preferably comprise providing a stream of the solution of the tranexamic acid to a precipitation chamber, providing a stream of the fluid anti-solvent to the precipitation chamber, and contacting the stream of the solution with the stream of the fluid anti-solvent within the precipitation chamber to precipitate said composition comprising particles of tranexamic acid within the precipitation chamber.

[0102] The anti-solvent may in principle be any fluid consistent with achieving desired particle formation. As is known in the art, an anti-solvent for precipitation is generally chosen such that the product, in this case the composition comprising particles of tranexamic acid, is substantially insoluble therein. The role of the anti-solvent is to extract the solvent from the solution of tranexamic acid and to precipitate desirable particles of tranexamic acid. Preferably, the fluid anti-solvent is carbon dioxide.

[0103] Preferably, the anti-solvent is a supercritical fluid, although in some embodiments near- critical fluids may also be suitable. A "supercritical fluid" is a fluid at or above its critical pressure (Pc) and critical temperature (Tc) simultaneously. In practice, the pressure of the fluid is likely to be in the range between 1.01 and 7.0 of its critical pressure, and its temperature in the range between 1.01 and 4.0 of its critical temperature (in Kelvin). However, some fluids (e.g., helium and neon) have particularly low critical pressures and temperatures, and may need to be used under operating conditions well in excess of those critical values, such as up to 200 times the relevant critical value. The term "near- critical fluid" encompasses both high pressure liquids, which are fluids at or above their critical pressure but below (although preferably close to) their critical temperature, and dense vapors, which are fluids at or above their critical temperature but below (although preferably close to) their critical pressure. By way of example, a high-pressure liquid might have a pressure between about 1.01 and 7 times its Pc, and a temperature between about 0.5 and 0.99 times its Tc. A dense vapour might, correspondingly, have a pressure between about 0.5 and 0.99 times its Pc, and a temperature between about 1.01 and 4 times its Tc.

[0104] The fluid anti-solvent and the solution of tranexamic acid may form a supercritical or near-critical mixture on contact. The fluid anti-solvent may preferably be carbon dioxide having a pressure of less than 200 bar absolute, preferably less than 150 bar absolute. The fluid anti-solvent may preferably be carbon dioxide having a pressure of from 50 to 175 bar absolute or from 75 to 150 bar absolute. The carbon dioxide may preferably have a temperature of from 35 °C to 80°C or from 40 °C to 70 °C, e.g. from 50 °C to 60 °C.

[0105] The fluid anti-solvent may have a density of less than 0.80 g / cm3, preferably less than 0.60 g / cm3. The fluid anti-solvent may have a density of from 0.20 to 0.80 g / cm3, preferably from 0.25 to 0.70 g / cm3, e.g., from 0.30 to 0.60 g / cm3.

[0106] Preferably, a high excess of the anti-solvent is contacted with the solution of the compound of tranexamic acid. For example, the ratio of the mass fraction of contacted anti-solvent to the mass fraction of contacted tranexamic acid solution may be 75 or more, preferably 100 or more, more preferably 120 or more. The ratio of the mass fraction of contacted anti-solvent to the mass fraction of contacted tranexamic acid solution may be from 75 to 300, preferably from 80 to 250, more preferably from 100 to 200, e.g., from 110 to 175.

[0107] Preferably, the solution (e.g., the stream of the solution) of tranexamic acid is contacted with the fluid anti-solvent (e.g. the stream of fluid anti-solvent) at a pressure of less than 200 bar absolute, preferably less than 150 bar absolute. Preferably, the solution (e.g., the stream of the solution) of tranexamic acid is contacted with the fluid antisolvent (e.g. the stream of fluid anti-solvent) at a pressure of from 50 to 175 bar absolute or from 75 to 150 bar absolute. Preferably, the solution (e.g., the stream of the solution) of tranexamic acid is contacted with the fluid anti-solvent (e.g., the stream of fluid anti-solvent) at a temperature of from 35 °C to 80°C or from 40 °C to 70 °C, e.g. from 50 °C to 60 °C. This may be achieved by maintaining the pressure and temperature in the precipitation chamber at the desired levels whilst the solution and anti-solvent are contacted.

[0108] The anti-solvent and the solution of tranexamic acid may be contacted in any manner consistent with desired particle formation. In general, to achieve precipitation, the antisolvent and solution are contacted such that extraction of a solvent system of the solution occurs by the action of the anti-solvent. Suitably, this may occur in the precipitation chamber, for example in which temperature and pressure are controlled to desired levels. Mixing energy may be provided by shear between the anti-solvent and the solution, as is known in the art. Advantageously, the anti-solvent and solution may be contacted such that dispersion and extraction of the solvent system occur substantially simultaneously by the action of the anti-solvent. Suitably, the energy of mixing may be arranged to provide a virtually instantaneous homogeneous fluid mixture of the anti-solvent and solution.

[0109] The stream of anti-solvent and the stream of solution of tranexamic acid may be introduced into the precipitation chamber via respective passages with respective outlets, the outlets being arranged relative to one another such that stream of antisolvent introduced through a first passage and the stream of solution of tranexamic acid introduced through a second passage contact each other in the precipitation chamber.

[0110] The stream of the solution of the compound of tranexamic acid and the stream of antisolvent may be provided to the precipitation chamber at substantially the same point. The stream of solution and the stream of anti-solvent may be co-fed into the precipitation chamber using a nozzle arrangement having co-axial passages which terminate adjacent to one another.

[0111] Preferably, the stream (or more than one stream) of anti-solvent is arranged to impinge on the stream (or more than one stream) of the solution. This arrangement advantageously provides high shear and thus a high degree of contact between the antisolvent and the solution.

[0112] However, any arrangement which provides for good levels of mixing and dispersion may be used, such as those disclosed in WO-95 / 01221, WO-96 / 00610, WO-98 / 36825, WO- 99 / 44733, WO-99 / 59710, WO-01 / 03821, and WO-03 / 008082, which are incorporated herein by reference.

[0113] The method may comprise contacting a relatively high velocity anti-solvent stream, with a relatively low velocity stream solution of tranexamic acid. The relative velocities of the two fluid streams may suitably be managed by varying the diameter and cross-sectional area of respective jets or nozzles for delivering the streams, and controlling the flow rate of each fluid stream. For example, the velocity of a stream may be controlled by an orifice plate of fixed diameter. This diameter may be arranged so as to maintain a set temperature and pressure on the upstream side of the orifice plate, while maintaining a specific flow rate through the orifice. The velocity of the resulting stream can be calculated using the density of the fluid upstream of the orifice plate (by referencing the fluid temperature and pressure), the mass flow of the fluid, the cross sectional area of the orifice, and the differential pressure across the orifice (equation given in Crystallization process in turbulent supercritical flows, Shekunov, B Yu, Hanna M, York P J, Crystal Growth, 198-199, 1345-1351 (1999)). The amount of kinetic energy suitable for mixing the two fluids and initiating supersaturation varies between each solute and each solvent mixture used. Preferably, the anti-solvent (e.g. CO2) stream velocity is at least 50 m / sec, more preferably at least 100 m / sec, still more preferably at least 200 m / sec. The anti-solvent stream velocity may preferably be in the range of from 50 to 500 m / sec, preferably from 100 to 400 m / sec, e.g., from 200 to 300 m / sec. The velocity of the solution of tranexamic acid is typically lower than the velocity of the anti-solvent stream and not critical to the invention. In an embodiment, the velocity ratio between the anti-solvent stream and the solution stream is in the range of from 100: 1 to 1200: 1, preferably from 250: 1 to 1000: 1, e.g., from 350: 1 to 600: 1.

[0114] Preferably, the anti-solvent stream (e.g. CO2) has a flow rate of at least 50 g / min, more preferably at least 100 g / min, still more preferably at least 150 g / min. The flow rate of the anti-solvent stream may preferably be in the range of from 50 to 500 g / min, preferably from 100 to 400 g / min, e.g., from 150 to 300 g / min.

[0115] In a preferred method, upon contacting the fluid anti-solvent with the solution of tranexamic acid, the solvent is extracted from the solution by the fluid anti-solvent to form a mixture of the solvent and the fluid anti-solvent, thereby precipitating said composition comprising particles of tranexamic acid, e.g., in the precipitation chamber. Preferably, the mixture of the solvent and the fluid anti-solvent are removed from the precipitation chamber, e.g., via a vent.

[0116] Preferably, the method further comprises recovering the composition comprising particles of tranexamic acid from the precipitation chamber. This may involve depressurisation of the precipitation chamber followed by removal of the composition comprising particles of tranexamic acid from the precipitation chamber.

[0117] The concentration of tranexamic acid in the solvent may be 5 mg / ml or greater, preferably 10 mg / ml or greater. The maximum amount of tranexamic acid is generally limited only by its solubility in the solvent system. The concentration of tranexamic acid in the solvent may be 70 mg / ml or less, suitably 20 mg / ml or less of the agent. Preferably, the concentration of tranexamic acid in the solvent may be from 5 mg / ml to 200 mg / ml, preferably from 10 mg / ml to 100 mg / ml, more preferably from 15 mg / ml to 50 mg / ml, e.g. from 15 mg / ml to 25 mg / ml. Concentrations may preferably be based on the volume of the solvent system at standard atmospheric temperature and pressure.

[0118] The solvent preferably comprises an organic solvent. Preferred organic solvents comprise alcohols such as a Ci-C6alkanol, preferably methanol, ethanol, propanol (e.g., isopropanol (IPA)) or a mixture thereof. Methanol may be particularly preferred. The solvent preferably further comprises an organic acid. The organic acid advantageously improves the solubility of tranexamic acid in the organic solvent. Preferred organic acids include acetic acid, formic acid, citric acid and ascorbic acid, preferably acetic acid (e.g. glacial acetic acid). A preferred solvent system comprises or consists of a C1-C3 alkanol (e.g. methanol) and acetic acid.

[0119] In solvents comprising an organic solvent and an organic acid, the ratio (by volume) of organic solvent (such as C1-C3 alkanol) to organic acid (such as acetic acid) may preferably be from 50: 1 to 1 : 1, more preferably from 20: 1 to 2: 1, still more preferably from 15: 1 to 5: 1. In some preferred methods, the solvent may be substantially devoid of water (e.g. does not contain water other than trace water present in the organic solvent and / or organic acid).

[0120] The method according to the third aspect of the invention provides good mass recovery of the product. Preferably, the composition comprising particles of tranexamic acid is prepared in yield of at least 25%, more preferably at least 50%, still more preferably at least 60%, yet more preferably at least 75%. Yields of up to 100% may advantageously be obtained, for example yields of from 50% to 98%, or from 70% to 95%. Yield is based on the mass of the recovered tranexamic acid particles, as a percentage of the mass of tranexamic acid starting material.

[0121] The method according to the third aspect of the invention preferably directly provides a composition comprising particles of tranexamic acid that are suitable for administration by inhalation without any further processing steps, i.e. they have suitable morphology and particle size characteristics to be used as a medicament without further processing of the particles. This does not preclude further steps that do not affect the nature (e.g. particle size / morphology characteristics) of the tranexamic acid particles, such as mixing with suitable pharmaceutical excipients or other drugs to provide a medicament product. Preferably, the method does not comprise milling, micronisation or spray drying.

[0122] Preferably, the composition comprising particles of tranexamic acid prepared by the method of the third aspect may be as hereinabove described with respect to the foregoing aspects of the invention. In particular, the composition comprising particles of tranexamic acid prepared by the method may preferably comprise (or consist of) the composition comprising particles of tranexamic acid according to the first aspect as hereinbefore described. Thus, preferred features of the composition comprising particles of tranexamic acid prepared by the method of the third aspect are as hereinbefore described with respect to the first aspect of the invention. In a fourth aspect, the invention provides a composition comprising particles of tranexamic acid obtained by a method according to the third aspect. Preferred features of the method by which the composition according to the fourth aspect is maintained are as hereinbefore described with respect to the third aspect of the invention. Preferred features of the composition according to the fourth aspect are as hereinbefore described with respect to the first aspect of the invention.

[0123] In a fifth aspect, the invention provides a pharmaceutical composition comprising (or consisting of) a therapeutically effective amount of a composition comprising particles of tranexamic acid according to any of the first, second and fourth aspects, e.g., the first aspect.

[0124] The pharmaceutical composition is preferably a dry powder composition. However, the pharmaceutical composition may take any suitable form known in the art. Suitably, the particles of tranexamic acid may be suspended in a non-solvent vehicle.

[0125] The pharmaceutical composition may further comprise a suitable excipient. Suitable amounts of excipient are known to a skilled person. For example, one or more excipients may be present in an amount of from 20 to 99.9% by weight of the total composition, preferably 50 to 99 % by weight of the total composition, suitably 60 to 95% by weight of the total composition. The excipient may be of conventional type and may be obtained by any suitable process. An example of a suitable excipient is inhalable lactose.

[0126] A preferred pharmaceutical composition does not, however, contain any excipients. Advantageously, the inventors have prepared a form of tranexamic acid that can be directly used as a pharmaceutical composition without the need for excipients. The tranexamic particles have an optimum morphology for use as a pharmaceutical composition, particularly for pulmonary administration (e.g., by inhalation or insufflation).

[0127] In a sixth aspect, the invention provides the composition according to any of the first, second, fourth and fifth aspects for use as a medicament. The use may preferably involve prevention or treatment of a condition (e.g., in a human or other mammal, preferably a human), that is alleviated by inhibition of fibrinolysis.

[0128] In a seventh aspect, the invention provides the composition according to any of the first, second, fourth and fifth aspects for use in the prevention or treatment of blood loss (e.g., in a human or other mammal, preferably a human). Blood loss may comprise internal and / or external bleeding, and may be chronic or acute. In an eighth aspect, the invention provides the composition according to any of the first, second, fourth and fifth aspects for use in the prevention or treatment of a disorder (e.g., in a human or other mammal, preferably a human) selected from the group consisting of: haemorrhage, trauma, uterine bleeding and bleeding disorders.

[0129] Examples of haemorrhage include (but are not limited to) post-partum haemorrhage and subarachnoid haemorrhage. Post-partum haemorrhage (PPH) is a particularly preferred disorder which can be effectively treated by the composition according to any of the first, second, fourth and fifth aspects of the invention. There are approximately 14 million cases of postpartum haemorrhage (PPH) per year worldwide. PPH is the leading cause of maternal mortality in low-income countries and the primary cause of nearly one quarter of all maternal deaths globally. Inhaled therapy provides the opportunity for rapid intervention in the event of postpartum haemorrhage in non-hospital settings. The present invention thereby provides a simple and potentially more effective alternative to intravenous infusion, in situations where attending personnel do not have the training or facilities to gain cannula access.

[0130] Examples of trauma include (but are not limited to) traumatic brain injury (including concussion), traumatic bleeding, battlefield trauma, stabbings and crush injuries.

[0131] Traumatic brain injury is a preferred disorder which can be treated by the composition according to the first, second, fourth and fifth aspects of the invention. Traumatic brain injury contributes to worldwide death and disability more than any other traumatic insult, affecting 10 million individuals annually. The CRASH-3 study demonstrated that early intervention (in under 3 hours) of tranexamic acid reduced deaths from brain injury. The present invention provides an opportunity for use of a safe, easily administered tranexamic acid formulation for this indication. For example, it is envisaged that the composition of the invention could find practical utility in traumatic sports injuries (e.g. concussion) via use in on-pitch interventions and head injury assessment protocols.

[0132] Battlefield trauma is another preferred disorder which can be treated by the composition according to the first, second, fourth and fifth aspects of the invention. 90% of deaths from battlefield trauma occur before the injured reaches a medical facility, and 90% of acute mortality is associated with haemorrhage. It is estimated that 25% of war deaths are medically preventable. Haemorrhage resulting from battlefield trauma (in excess of 20-30% of blood volume) results in peripheral shutdown, leading to difficulty in gaining venous access. Combined with the challenges of intramuscular injection, the availability of a safe and effective treatment that can be readily administered via pulmonary delivery is clearly highly desirable and advantageous. Similar vascular responses occur in different types of major trauma (e.g. stabbings, crush injuries) and so similar benefits are envisaged.

[0133] Examples of uterine bleeding include (but are not limited to) heavy menstrual bleeding (menorrhagia) and abnormal uterine bleeding. Menorrhagia is a preferred disorder which can be treated by the composition according to the first, second, fourth and fifth aspects of the invention. Tranexamic treatment for menorrhagia is currently available in tablet form for oral administration. The present invention provides an inhalable form of tranexamic acid which can be used to provide fast onset of action and rapid symptomatic relief. It may be combined with existing oral therapies for ongoing control.

[0134] Examples of bleeding disorders include (but are not limited to) haemophilia and von Willebrand disease.

[0135] In a ninth aspect, the invention provides a method of treating a disorder in a patient (e.g., a human or other mammal, preferably a human), the method comprising administering to said patient a therapeutically effective amount of the composition according to any of the first, second, fourth and fifth aspects. The disorder may suitably be as hereinbefore described with respect to any of the sixth to eighth aspects of the invention.

[0136] In aspects six to nine of the invention hereinbefore described, the use or treatment preferably comprises administration of a therapeutically effective amount of the composition to a patient (e.g., human or other mammal, preferably a human) in need thereof, wherein said administration is by pulmonary administration. Preferably, said administration is by inhalation or insufflation, more preferably by inhalation. The administration may be local or systemic but is preferably systemic. Administration by inhalation may be via a single inhalation or via multiple inhalations (e.g. two or more successive breaths). The total amount of the composition administered may preferably be as described below in relation to the tenth aspect of the invention.

[0137] The use or treatment in aspects six to nine of the invention may further comprise administration of tranexamic acid via a different route (e.g. orally or intravenously), for example following initial pulmonary administration. The use or treatment may further comprise administration of another drug (e.g. a different antifibrolytic drug), for example following initial administration of tranexamic acid. Advantageously, initial pulmonary administration of tranexamic acid in accordance with the present invention can provide rapid symptomatic relief (e.g. to "buy time"), followed by use of another treatment (e.g. oral or intravenous administration of tranexamic acid, or another drug) for longer term treatment.

[0138] The disorder in aspects six to nine of the invention may be one requiring rapid relief, e.g. rapid symptomatic relief, or fast onset of the tranexamic acid. The treatment may thus preferably be for providing rapid relief, e.g. rapid symptomatic relief, or onset of the tranexamic acid, within a short period of time, e.g. less than 20 minutes, or less than 10 minutes, or less than 5 minutes following administration. Rapid relief or fast onset may, for example, be defined as achieving at least 50% of peak plasma exposure to the tranexamic acid, more preferably at least 70% of peak plasma exposure to the tranexamic acid, within the relevant time. Additionally or alternatively, rapid relief or fast onset may be defined as an improvement of at least 10%, preferably at least 20%, more preferably at least 30% or even at least 40% in at least one grading system associated with the disorder within the relevant time.

[0139] In a tenth aspect, the invention provides the composition according to any of the first, second, fourth and fifth aspects in an amount of at least 50 mg, preferably at least 200 mg, more preferably at least 400 mg, e.g. at least 500 mg, at least 1 g or even at least 2 g.

[0140] In an eleventh aspect, the invention provides an inhalation or insufflation device having therein the composition according to any of the first, second, fourth and fifth aspects. The device is preferably an inhalation device, e.g., an inhaler such as a metered dose inhaler or a dry powder inhaler. More preferably, the device is a dry powder inhaler. The dry powder inhaler may have therein a capsule containing the composition according to any of the first, second, fourth and fifth aspects. The inhalation or insufflation device (e.g. the dry powder inhaler) may be a single dose device or a multi-dose device. Preferably, the device is a multi-dose dry powder inhaler, such as a breath-actuated multi-dose dry powder inhaler, e.g. an Orbital™ inhaler.

[0141] Examples

[0142] For all examples the starting material used was tranexamic acid obtained from Sigma Aldrich (97% purity). Acetic acid was commercially available glacial acetic acid.

[0143] Particle size analysis was carried out using a Sympatec HELOS / KF Analyser with RODOS dry powder dispenser fitted with ASPIROS micro-dosing unit. The measuring range was 0.2 to 87.5 pm.

[0144] Aspect ratios (range and average) were measured from SEM images. In each case over 100 particles were measured. Examples 1 - 4 Comparative Example (Conventional crystallisation and millinq / micronisation)

[0145] Example 1

[0146] Figure 1 shows a SEM (HIROX SH 4000M Scanning Electron Microscope and SEC MCP- 100P ion beam sputter coater) of tranexamic acid starting material obtained from Sigma Aldrich, 97% purity. The particles of the starting material range exhibit a wide range of particle sizes, up to sizes larger than 100 microns, irregular morphology and evidence of agglomeration with smaller particle cohering to the surfaces of larger particles. Formal particle size analysis could not be carried out as the particle sizes of the sample were too large for the range of the apparatus (0.2 to 87.5 pm), meaning that accurate measurements of particle size parameters (Di0, D50, D90, VMD) could not be obtained. The aspect ratio range was 1 : 1 to 1 : 12, with an average aspect ratio of 1:5. Particle sizes of up to 1200 pm in maximum length were observed. Such features indicate that it is not possible to use such material unchanged when formulating powdered products for respiratory drug delivery.

[0147] Example 2

[0148] Figure 2 shows a SEM of a tranexamic acid powder prepared by conventional solvent evaporation crystallisation at ambient temperature from a solution of tranexamic acid dissolved in methanokacetic acid (9: 1 v / v) solution. Large particles are observed with similar particle characteristics to those described above for the starting material obtained from Sigma Aldrich. Formal particle size analysis could not be carried out as the particle sizes of the sample were too large for the range of the apparatus (0.2 to 87.5 pm), meaning that accurate measurements of particle size parameters (Di0, D50, D90, VMD) could not be obtained. The aspect ratio range was 1 : 1 to 1 : 16, with an average aspect ratio of 1 :7. Particle sizes of up to 1500 pm in maximum length were observed.

[0149] Example 3

[0150] A sample of tranexamic acid was jet milled using a Food Pharma Systems Labo Mill (serial number FP3241) with the jet mill set to 2 bar pressure for grinding. Whilst inhalable sized particles were generated, the SEM (Figure 3) illustrates that the powder from the high energy milling process is made up of irregular shaped and sized particle as a result of uncontrolled particle fracture and breakage. Smaller particles are shown to be cohering to the surfaces of larger particles and there is evidence of agglomeration. The powder also exhibited static charge leading to cohesive flow behaviour. The sample exhibited a Di0of 0.9 pm, a D50of 2.4 pm, a D90of 5.9 pm and a VMD of 3.0 pm. 8 vol% of particles exhibited a particle size of greater than 6 pm. The aspect ratio range was 1 : 1 to 1:9, with an average aspect ratio of 1:5. Particle sizes of up to 30 pm in maximum length were observed.

[0151] Example 4

[0152] Figure 4 shows the particle size distribution of the powder produced in Example 3 (Sympatec Helos fitted with a RODOS dry powder dispenser at 2 bar aerosolization pressure). This sample of milled tranexamic acid exhibits a broad size distribution in with a relatively high percentage (20%) of particles larger than 5 microns, confirming that powders prepared using milling processes are unsuitable for delivering high particle deposition on administration via the pulmonary route.

[0153] D50, D90and VMD *Sympatec Helos fitted with RODOS dry powder dispenser at 2 bar aerosolization pressure, n=3

[0154] Examples 5 to 26

[0155] Experiments were conducted with the object of forming advantageously inhalable or insufflable particles of tranexamic acid using supercritical anti-solvent (SAS) precipitation

[0156] The method used to generate particles of inhalable tranexamic acid was a SAS (Supercritical Anti-Solvent) process.

[0157] For the process the antisolvent and drug (in this case tranexamic acid) solution are introduced continuously via respective passages into a pressurised precipitation vessel (also referred to as a precipitation chamber). The flow rates of each feed line, typically carbon dioxide as the antisolvent and a solution of drug in an organic solvent, are monitored. The pressure in the precipitation vessel is controlled and maintained by a back pressure regulator connected in line at the single outlet vent passage from the precipitation vessel. The temperature of the whole assembly is controlled, typically using an oven when at laboratory and small-scale operation. In this way, supercritical or near critical antisolvent fluid conditions are created within the precipitation vessel.

[0158] The outlets of the two feed lines enter into the precipitation vessel at substantially the same point which is where the antisolvent and solution meet. In order to achieve a high degree of contact between the antisolvent and solution, mixing and dispersion, the antisolvent and solution are, for example, co-fed into the precipitation vessel using a nozzle arrangement having co-axial passages which terminate adjacent to one another. Alternatively, one or more streams of the antisolvent can be arranged to impinge on a stream of the solution to provide a high degree of contact between the antisolvent and the solution, mixing and dispersion. Other contact, mixing and dispersion arrangements are known with examples of suitable equipment, inter alia, from WO95 / 01221, W096 / 00610, WO98 / 36825, WO-99 / 44733, WO99 / 59710, W001 / 03821, and W0008082, which are incorporated herein by reference.

[0159] Following contact, mixing and dispersion of the antisolvent and solution under supercritical or near critical antisolvent fluid conditions, the solvent from the solution is extracted by, and dissolved in, the supercritical fluid or near critical supercritical fluid to form respectively a supercritical solution or near critical antisolvent solution which exits from the precipitation vessel via the vent line. Following the extraction of the solvent, the drug particles precipitate and are retained in the precipitation vessel and collected, typically in a collecting device such as a basket. The precipitated particulate powder is subsequently recovered following depressurisation of the precipitation vessel.

[0160] For each example, tranexamic acid was dissolved in an organic solvent mixture containing an organic acid.

[0161] A stream of the solution of tranexamic acid was contacted with a stream of supercritical or near critical carbon dioxide in a precipitation chamber, as described above, to form particles of tranexamic acid.

[0162] The effect of a range of particle formation conditions on particle precipitation was examined in Examples 5 to 26, in which particle formation conditions were varied.

[0163] Particle formation conditions that were varied are listed in Table 1, together with particle characterisation results. In more detail, Table 1 refers to the following particle formation conditions / results:

[0164] - The volume of the precipitation chamber ("Chamber volume"), indicated in millilitres (ml).

[0165] - The type of mixing nozzle arrangement ("Nozzle Type") - in a first nozzle arrangement (Type I) carbon dioxide was arranged to impinge on a stream of the solution to provide high shear, whereas in a second nozzle arrangement the carbon dioxide and the solution were co-fed into the precipitation chamber via a nozzle having co-axial passages which terminate adjacent to one another, providing less shear, there being a first variant with a carbon dioxide orifice diameter of 750 micrometres (Type II) and a second variant with a carbon dioxide orifice diameter of 500 micrometres (Type III).

[0166] - The concentration of tranexamic acid in the organic solution ("Drug Solution Concentration"), indicated in milligrams per millilitre of organic solvent mixture (mg / ml).

[0167] - The temperature of the stream of carbon dioxide ("CO2T") indicated in degrees Celsius (°C)

[0168] - The atmospheric pressure of the stream of carbon dioxide ("CO2p") indicated in bars (bar)

[0169] - The density of the stream of carbon dioxide ("CO2Density") indicated in grams per cubic centimetre (g / cm3)

[0170] - The flow rate of the solution of tranexamic acid into the precipitation chamber ("Drug Solution Flow") indicated in grams per minute (g / min)

[0171] - The flow rate of carbon dioxide into the precipitation chamber ("CO2Flow") indicated in grams per minute (g / min)

[0172] - The velocity of the carbon dioxide stream entering the precipitation chamber ("CO2Velocity") indicated in metres per second (m / s)

[0173] - The ratio ("Mass Fraction Ratio Flows") of the mass fraction of the carbon dioxide flow into the precipitation chamber (CO2Flow I [CO2Flow +Drug Solution Flow]) over the mass fraction of the solution of tranexamic acid solution flow into the precipitation chamber (Drug Solution Flow / [CO2Flow +Drug Solution Flow]), dimensionless.

[0174] - The particle diameter where a cumulative particle diameter distribution of the precipitated tranexamic acid particles reaches 50% by volume, i.e. 50% by volume of the particles have a smaller diameter than this value, and 50% by volume of the particles have a larger diameter than this value ("D50"), indicated in micrometres (pm).

[0175] - The particle diameter where a cumulative particle diameter distribution of the precipitated tranexamic acid particles reaches 90% by volume, i.e. 90% by volume of the particles have a smaller diameter than this value, and 10% by volume of the particles have a larger diameter than this value ("D90"), indicated in micrometres (pm). The volume mean diameter ("VMD") of the precipitated tranexamic acid particles, indicated in micrometres (pm).

[0176] Tab e 1

[0177] Table 1 continued

[0178] D50, D90and VMD *Sympatec Helos fitted with RODOS dry powder dispenser at 2 bar aerosolization pressure

[0179] Initial tranexamic acid experiments from SAS produced a variety of different types of morphologies. These included 'needle-like' (acicular), plate, spherulite, lath, spherical and tabular morphologies. Under some experimental conditions agglomerated (fused particles) and conglomerates (mixture of two or more particle morphologies) were produced. The control of particle morphology presented challenges in the context of precipitation of inhalable or insufflable particles, together with achieving uniform in particular particles with D50and D90percentiles between 1 to 4 pm and 2 to 10 pm respectively and volume mean diameter of 1-4 pm

[0180] Examples 5 - 19 produced fine powders but with uncontrolled particle habits and shapes and / or particle size distributions outside the range required for powder delivery to the lungs. Observed shapes included plate (Example 18 - see Figure 18), spherulite (Example 7 - see Figure 7), and tabular (Example 21 - see Figure 21) morphologies.

[0181] Under certain process conditions unfavourable conglomerates (mixture of two or more particle morphologies) such as Example 5 (Figure 5 shows a mixture of 'needle-like' (acicular), spherulite and spherical particles), and Example 16 (Figure 16 shows a mixture of lath and spherulite particles), and agglomerated (fused particles) such as Example 12 (see Figure 12) were produced. Alternative nozzle configurations did not result in acceptable powders (Examples 17 and 18).

[0182] Example 21

[0183] For Example 21, it was surprisingly found that fine, free flowing powders with controlled particle size distributions and morphology were obtained. SEM examination of the particles of Example 21 show uniform, smooth surfaced crystalline particles with tabular morphology (Figure 21) with narrow particle size distribution. Notably, these particles have a different shape to the milled particles of Figure 3 and do not suffer from the agglomeration seen in the milled particles.

[0184] The particle size distribution for this material is more regular, with a narrower particle size spread (see Figure 27) when compared with milled material (see Figure 4). All particles appear as distinct primary particles without any 'smaller' particle coherence to the surfaces of other particles, a reflection of the improved and smoother surface topography, which facilitates particle aerosolisation. Interparticle agglomeration is absent.

[0185] Particle size analysis for Example 21 particles was conducted on a Sympatec Helos laser diffraction particle size analyser fitted with a RODOS dry powder dispenser using 2 bar aerosolization pressure. Data shown in Figure 27 and in the table below show that inhalable sized particles with a tight size distribution were produced. aerosolization pressure, n=3

[0186] The aspect ratio range was 1 : 1 to 1:4, with an average aspect ratio of 1 :2.

[0187] Samples of Example 21 powder, was stored under ambient conditions in sealed, 20 ml glass screw cap scintillation vials, was found to be physically stable after 5 years. The SEM in Figure 28 demonstrates a similar morphology of particles and size distribution for the stored powder, with no evidence of solvent bridging or growth to those for the 'as prepared' sample (see Figure 21). Data given in Figure 29 and in the table below confirm that there has been no particle growth or agglomeration over the storage time of 5 years (compare Figure 27). aerosolization pressure, n=3

[0188] Chemical purity of Example 21 powder was assessed by High Pressure Liquid Chromatography using an Agilent 1100 series HPLC with a UV-visible detector (220 nm). The HPLC method used complied with the Ph Eur monograph 0875. (Column: ODS (C18) 250 x 4.6 mm, 5 pm, 80 A pore size protected with a pre-column; mobile phase consisted of 11 g of anhydrous sodium phosphate monobasic, 5 ml triethylamine, 1.4 g sodium dodecyl sulphate in 500 ml deionised water, pH adjust to 2.5 with o-phosphoric acid, fill to 600 ml with deionised water, then add 400 ml methanol and mix; flow rate of 0.9 ml / min and injection volume 20 pl). The purity of Example 21 processed material at equivalent solution concentration to the calibration sample (prepared from as supplied tranexamic acid material, 97% purity) shows that processing by SAS did not degrade tranexamic acid (similar retention time and area for similar solution concentration) obtained (see Figures 30a and 30b).

[0189] By examining the experimental space for scaling up the SAS process based on Experiment 21, it was surprisingly found that fine, free flowing powders with controlled particle size distributions and morphology were obtained for Experiments 22 - 26. In addition, these Examples show that inhalable or insufflable particles of tranexamic acid, in particular particles with D50and D90percentiles between 1 to 4 pm and 2 to 10 pm and volume mean diameter of 1.7 m to 2.0 pm were produced. Processing conditions for Examples 22 - 26 are identified as:

[0190] - the ratio of the mass fraction of contacted carbon dioxide to the mass fraction of contacted tranexamic acid solution was 120 or more and the carbon dioxide had a density in the range of from 0.40 to 0.55 g / cm3

[0191] - the ratio of the mass fraction of contacted carbon dioxide to the mass fraction of contacted tranexamic acid solution was 120 or more.

[0192] Surprisingly, it was found that at higher carbon dioxide flow (ratio of mass fraction ratio of carbon dioxide flow to mass fraction of tranexamic acid of 120 or more), it was possible to produce inhalable particles at temperatures 50°C and 60°C, pressures of 110 bar and 125 bar, and solution flow rate of 1.64 g / ml. Additionally, at lower carbon dioxide flow, a ratio of the mass fraction of carbon dioxide to the mass fraction of tranexamic acid solution more than 80 surprisingly led to in advantageous particle formation.

[0193] Examples 25 and 26 show favourable tabular particles and particle size distribution (see Figures 25 and 26). Optimal scale-up process conditions demonstrate that favourable particle characteristics such as particle morphology and particle size distribution are maintained as the batch size is increased.

[0194] Examples 24 (5 g batch), 25 (10 g batch) and 26 (see Figures 24, 25 and 26) show that powders from pilot plant scale optimal processing conditions demonstrate good reproducibility between samples. Particles exhibit values D50(1.59-1.87 pm) and D903.15- 3.59 pm) and controlled uniform tabular morphology which is similar to data for Example 21, produced at smaller scale (Example 21 - D502.04 pm and D904.90 pm).

[0195] Representative confirmation of chemical and solid state identity of the powder samples prepared at scale-up were assessed by Powder X-Ray Diffraction (PXRD, Rigaku MiniFlex600 Powder X-Ray Diffractometer, scan range 3°-40°, step size 0.020°, scan speed 2° / min, 40kV, 15 mV). There is only one known polymorphic form of tranexamic acid (Traxidot Public assessment report - scientific discussion, DK / H / 2590 / 001 / MR, 31 January 2017). Figure 33 shows two representatives PXRD profiles of tranexamic acid precipitated in Examples 25 and 26, respectively.

[0196] Example 26 powder was found to be physically stable when stored in 20 ml glass screw cap scintillation vials for 5 years at room temperature, see Figure 38A and 38B. Figure 38B shows similar morphology and size distribution to Figure 38B (SEM analysis after Example 30 was prepared), with no evidence of solvent bridging or particle growth. Whilst particle size analysis was not carried out on Example 20, SEM images (Figure 20) indicated that this sample had desirable morphology, shape and particle size characteristics similar to those of Examples 21 to 26.

[0197] Example 21 (small scale) had a yield of 66%. Examples 22 to 26 (pilot plant scale) had yields of 61 to 88%.

[0198] Examples 20 to 26 demonstrate that conditions have been developed that surprisingly provide tranexamic acid particles having an advantageous combination of particle characteristics (morphology / shape and particle size distribution) for delivery to the deep lung compartments. Without wishing to be bound by theory, it is believed that the combination of solvent system and CO2velocity contribute to the desired characteristics.

[0199] Example 27 Bioavailabilitv study

[0200] Two 5 gram samples from Examples 23 and 24 were blended with a Turbula® mixer (Willy A. Bachofen AG, Germany) for 10 minutes. The blended powder was analysed and characterised prior to dispatch by SEM analysis, PSA analysis using Sympatec 2 bar aerosolization pressure using R1 range (0.18-35 pm), n=6), and PXRD analysis, see Figures 35A, 35B and 35C, respectfully. It can be seen from Figure 35B that no particles exhibited a particle size of greater than 6 pm.

[0201] Eight Dawkley male rats, average weight 200g, were randomly divided into two groups of four (Test - inhalation, and Control -oral). The administered oral dose (60mg / kg) was calculated by reference to the oral clinical adult dose. Administration was via a gastric tube using 10ml of a 6mg / ml aqueous solution of tranexamic acid. The inhaled dose was calculated on the actual aerosol atomisation concentration (8.62mg / kg) delivered into the rat exposure chamber. The powder aerosol was generated from the blended powder bed using compressed air. The aerosol cloud formed was passed into a carousel-style exposure chamber with constrained rats allowed to inhale the powder aerosol for 10 minutes.

[0202] Blood samples were collected from the control (oral) group at 0.25h, 0.5h, Ih, 2h, 4h, 6h, 8h and 24h after administration. For the test (inhalation) group, blood samples were collected at the following time points: immediately at the end of administration (10 minutes), and 0.25h, 0.5h, Ih, 2h, 4h, 6h, 8h and 24h after administration.

[0203] Aerosol administration produced a rapid rise in tranexamic acid plasma level compared with slower systemic absorption following oral administration (Figures 36 and 37). Data demonstrate that systemic uptake after powder aerosol administration was rapid with up to 58% peak levels at the first measurable time point at the end of exposure (10 minutes). Average time to peak concentration was 1.1 h (SD 0.77) for the powder aerosol administration and slower at 2.0 h following oral administration. Figure 36 shows pharmacokinetic data for Control Group (administered intragastrically 60 mg / kg dose) and Figure 37 shows pharmacokinetic data for Test Group (administered by inhalation, 8.62 mg / kg dose). The relative bioavailability of the aerosol inhalation animal group against the oral administration group was 138%. These findings demonstrate that aerosol drug delivery via the respiratory route provides both rapid systemic uptake and improved bioavailability of tranexamic acid compared with oral administration of the tranexamic acid.

[0204] Example 28 Next Generation Impactor (NGI) study

[0205] Aerodynamic Particle Size Distribution (APSD) is identified as a Critical Quality Attribute (CQA) for Orally Inhaled and Nasal Drug Products (OINDPS). The APSD defines how particles behave in a moving air stream and is relevant to understanding likely lung deposition and hence potential drug efficacy. The NGI is a high performance, precision cascade impactor, and is ideal for testing at all relevant flow rates specified in the relevant pharmacopoeias.

[0206] Drug particles between 5 and 10 pm will generally deposit in the upper airways, 0.5-5 pm will sediment in the deep lung, whilst those of <0.5 pm will undergo Brownian motion and are likely to be exhaled by patients. The larger the GSD, the more sites that the aerosol will deposit in the respiratory tract. Ideally aerosols should have a GSD of <2 pm and be as close to monodispersity as possible to increase deposition at the desired site of action, in turn increasing efficacy of the treatment.

[0207] Next Generation Impactor (NGI) studies of the aerosolization behaviour of Example 21 were conducted. In particular the studies determined the total emitted dose (TED), fine particle dose (FPD), fine particle fraction as a percentage of TED (FPF%), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of pure SAS tranexamic acid. The Aerodynamic Particle Size Distribution for Example 21 was performed using an NGI (Figure 31, Table 2).

[0208] For the NGI studies 8 mg of Example 21 powder was weighed directly into a size 3 Qualicaps-V®-1 capsule and delivered with a high resistance Plastiape RS-01™ device and analysis of Example 21 was conducted in duplicate. Each plate was quantitively washed with deionised water and transferred to a volumetric flask of known volume and made to the mark with deionised water. The samples were then analysed by the HPLC method outlined above.

[0209] Table 2. NGI operating conditions and results

[0210] Data provided in Table 2 shows good FPD and FPF. The high FPF (see Figure 31) and GSD <2 pm value indicate a potential for good lung deposition and fast onset of action. The MMAD correlates closely to preliminary particle size data for Example 27 generated on the Sympatec Helos fitted with a RODOS dry powder dispense (monomodal size distribution,

[0211] VMD = 2.0 pm). The potential for excellent APSD and fast onset of action is demonstrated by the findings of the bioavailability study, see Figure 37). References

Claims

CLAIMS1. A composition comprising particles of tranexamic acid, the particles of tranexamic acid having a D90of 5.0 pm or less.

2. The composition of claim 1, wherein the particles of tranexamic acid are obtainable by supercritical anti-solvent (SAS) precipitation.

3. The composition of claim 1 or claim 2, wherein the particles of tranexamic acid have one or more of the following particle size characteristics: i. a Dio of from 0.1 pm to 2.0 pm; ii. a D50of from 1.0 pm to 3.0 pm; iii. a D90of from 2.0 pm to 5.0 pm; and iv. an aspect ratio of from 1: 1 to 5: 1.

4. The composition of any preceding claim, wherein the particles of tranexamic acid have a monomodal particle size distribution.

5. The composition of any preceding claim, wherein less than 10 vol% of the particles of tranexamic acid have a particle size of greater than 6 pm.

6. The composition of any preceding claim, wherein the particles of tranexamic acid are in crystalline form.

7. The composition of any preceding claim, wherein the particles of tranexamic acid are substantially devoid of amorphous material.

8. The composition of any preceding claim, wherein the particles of tranexamic acid have not been milled, micronized or spray-dried.

9. A method of preparing a composition comprising particles of tranexamic acid, the method comprising contacting a fluid anti-solvent with a solution comprising tranexamic acid in a solvent, to precipitate said particles of tranexamic acid.

10. The method of claim 9, wherein the anti-solvent is a supercritical fluid.

11. The method of claim 9 or claim 10, wherein the anti-solvent is carbon dioxide, preferably having a pressure in the range of from 75 to 150 bar absolute and a temperature in the range of from 35 to 80 °C.

12. The method of any of claims 9 to 11, wherein the anti-solvent is in the form of a stream, the stream of anti-solvent having a velocity of at least 50 m / sec.

13. The method of any of claims 9 to 12, wherein one or more streams of the anti-solvent are arranged to impinge on a stream of the solution.

14. The method of any of claims 9 to 13, wherein the anti-solvent is contacted with the solution at a temperature of from 35 °C to 80 °C and / or at a pressure of from 75 bar to 150 bar absolute.

15. The method of any of claims 9 to 14, wherein the solvent comprises an organic solvent and an organic acid.

16. The method of any of claims 9 to 15, wherein the composition comprising particles of tranexamic acid is the composition according to any of claims 1 to 8.

17. A composition comprising particles of tranexamic acid, wherein said composition is obtained by the method according to any of claims 9 to 16.

18. A pharmaceutical composition comprising a therapeutically effective amount of a composition according to any of claims 1 to 8 and 17.

19. The composition according to any of claims 1 to 8, 17 and 18, for use as a medicament.

20. The composition according to any of claims 1 to 8, 17 and 18, for use in the prevention or treatment of blood loss.

21. The composition according to any of claims 1 to 8, 17 and 18, for use in the prevention or treatment of a disorder selected from the group consisting of: haemorrhage, trauma, uterine bleeding and bleeding disorders.

22. The composition for use according to claim 21, wherein the disorder is post-partum haemorrhage, trauma selected from traumatic brain injury and battlefield trauma, or menorrhagia.

23. The composition for use according to claim 21, wherein the disorder is post-partum haemorrhage.

24. The composition for use according to any of claims 19 to 23, further comprising administration of a therapeutically effective amount of the composition to a patient in need thereof, wherein said administration is by pulmonary administration, preferably by inhalation.

25. An inhalation or insufflation device having therein the composition according to any of claims 1 to 8, 17 and 18.

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