Tranexamic acid composition

Abstract

Disclosed are compositions comprising tranexamic acid particles having a D 90 of 5.0 µm or less, methods of making the compositions, uses of the compositions, and devices containing the compositions.

Description

Technical Field

[0001] This invention relates to compositions comprising tranexamic acid particles. The invention also relates to methods for preparing said compositions, uses of said compositions, and apparatus containing said compositions. Background Technology

[0002] Tranexamic acid was invented in the early 1960s by Shosuke and Utako Okamoto, who reported the invention of 1-(aminomethyl)-cyclohexane-4-carboxylic acid (AMCHA), a compound now known as tranexamic acid (Brenner). Tranexamic acid is a synthetic analog of the amino acid lysine that blocks the conversion of plasminogen to plasmin and inhibits the binding of plasmin to fibrin, thereby stabilizing the fibrin matrix and reducing bleeding (O'Neil).

[0003] U.S. Patent 3,950,405 discloses trans-4-(aminomethyl)cyclohexanecarboxylic acid, commonly known as tranexamic acid. Tranexamic acid can be prepared, for example, by hydrogenation of trans-4-cyanocyclohexanecarboxylic acid or its lower alkyl esters under high pressure and high temperature, as described in U.S. Patent 3,950,5405. Improved methods for producing tranexamic acid have been identified, such as those described in WO 2015 / 104721.

[0004] Acute trauma is a common cause of death across all age groups and is associated with a high risk of death; time is crucial for treating life-threatening bleeding. The landmark CRASH-2 (randomized clinical trial of antifibrinolytic agents in severe bleeding), initiated in 2005, demonstrated that tranexamic acid significantly reduced bleeding-related deaths and all-cause mortality without increasing vascular occlusion events. The reduction in mortality was greatest when tranexamic acid was administered within 3 hours of injury. Administration after 3 hours showed no benefit in reducing mortality. Based on the results of the CRASH-2 trial, tranexamic acid was included in the World Health Organization (WHO) Essential Medicines List and incorporated into trauma guidelines in many countries worldwide (Brenner et al.). The CRASH-2 trial confirmed the efficacy of tranexamic acid in acute traumatic bleeding, showing that administration within three hours of the event reduced mortality by one-third (Cai et al. 2020, Brenner et al., 2019). During the CRASH-2 study, the landmark WOMAN (World Antifibrinolytic Drug for Pregnant Women) trial was launched in 2009. The WOMAN study showed that tranexamic acid had a survival benefit in patients with postpartum hemorrhage without increasing thromboembolic events (Brenner et al., 2019).

[0005] The World Health Organization (WHO) recommends tranexamic acid as a first-line treatment for postpartum hemorrhage (Vogel et al., 2018). In clinical settings, injectable products provide rapid systemic therapeutic tranexamic acid blood levels. Oral tablet formulations take >1 hour and 2–4 hours, respectively, to reach therapeutically effective blood levels (10 mg / L) and maximum levels (Grassin-Delyle et al., 2022), and are therefore not suitable for rapid emergency treatment.

[0006] Postpartum hemorrhage requires emergency treatment because patients with postpartum hemorrhage can die rapidly from hemorrhagic bleeding, and tranexamic acid, a drug recommended by the WHO, is most effective when administered early (Vogel at al 2018). In clinical situations, intravenous injections of tranexamic acid (such as Celtranz) can be administered. TM However, alternative routes of administration are needed to address the large number of non-clinical emergencies in order to improve accessibility and shorten treatment time (Vogel et al, 2018).

[0007] Therefore, there is a need for alternative forms of tranexamic acid that can provide rapid onset of action and are suitable for use outside of clinical settings. Summary of the Invention

[0008] In a first aspect, the present invention provides a composition comprising tranexamic acid particles, wherein the tranexamic acid particles have a D 90 It is 5μm or smaller.

[0009] In a second aspect, the present invention provides a composition comprising tranexamic acid particles as described above, wherein the tranexamic acid particles are obtained by supercritical antisolvent (SAS) precipitation.

[0010] In a third aspect, the present invention provides a method for preparing a composition comprising tranexamic acid particles, the method comprising contacting a fluid antisolvent with a solution comprising tranexamic acid in a solvent to precipitate the tranexamic acid particles.

[0011] In a fourth aspect, the present invention provides a composition comprising tranexamic acid particles, said composition being obtained by the method according to the third aspect.

[0012] In a fifth aspect, the present invention provides a pharmaceutical composition comprising (or consisting of) a therapeutically effective amount of the composition comprising tranexamic acid particles according to any one of the first, second and fourth aspects.

[0013] In a sixth aspect, the present invention provides a composition according to any one of the first, second, fourth and fifth aspects, for use as a medicine.

[0014] In a seventh aspect, the present invention provides a composition according to any one of the first, second, fourth and fifth aspects for use in preventing or treating blood loss.

[0015] In an eighth aspect, the present invention provides a composition according to any one of the first, second, fourth and fifth aspects for use in preventing or treating a condition selected from bleeding, trauma, uterine bleeding and bleeding disorders.

[0016] In a ninth aspect, the present invention provides a method for treating a patient’s ailment, the method comprising administering to the patient a therapeutically effective amount of the composition according to any one of the first, second, fourth and fifth aspects.

[0017] In a tenth aspect, the present invention provides a composition according to any one of the first, second, fourth and fifth aspects, in a content of at least 50 mg.

[0018] In an eleventh aspect, the present invention provides an inhalation or blowing device having a composition according to any one of the first, second, fourth and fifth aspects. Attached Figure Description

[0019] One or more embodiments of the invention will now be described by way of example only, with reference to the accompanying drawings, wherein:

[0020] Figure 1 This is a SEM image of tranexamic acid provided as is.

[0021] Figure 2 This is a SEM image of tranexamic acid formed by evaporation and crystallization from a methanol:acetic acid (9:1 v / v) solution using a conventional solvent.

[0022] Figure 3 This is a SEM image of tranexamic acid (provided as is) particles after grinding.

[0023] Figure 4 This is a particle size analysis of tranexamic acid particles after grinding.

[0024] Figure 5 This is a SEM image of the tranexamic acid precipitated in Example 5.

[0025] Figure 6 This is a SEM image of the tranexamic acid precipitated in Example 6.

[0026] Figure 7 This is a SEM image of the tranexamic acid precipitated in Example 7.

[0027] Figure 8 This is a SEM image of the tranexamic acid precipitated in Example 8.

[0028] Figure 9 This is a SEM image of the tranexamic acid precipitated in Example 9.

[0029] Figure 10 This is a SEM image of the tranexamic acid precipitated in Example 10.

[0030] Figure 11 This is a SEM image of the tranexamic acid precipitated in Example 11.

[0031] Figure 12 This is a SEM image of the tranexamic acid precipitated in Example 12.

[0032] Figure 13 This is a SEM image of the tranexamic acid precipitated in Example 13.

[0033] Figure 14 This is a SEM image of the tranexamic acid precipitated in Example 14.

[0034] Figure 15 This is a SEM image of the tranexamic acid precipitated in Example 15.

[0035] Figure 16 This is a SEM image of the tranexamic acid precipitated in Example 16.

[0036] Figure 17 This is a SEM image of the tranexamic acid precipitated in Example 17.

[0037] Figure 18 This is a SEM image of the tranexamic acid precipitated in Example 18.

[0038] Figure 19 This is a SEM image of the tranexamic acid precipitated in Example 19.

[0039] Figure 20 This is a SEM image of the tranexamic acid precipitated in Example 20.

[0040] Figure 21 This is a SEM image of the tranexamic acid precipitated in Example 21.

[0041] Figure 22 This is a SEM image of the tranexamic acid precipitated in Example 22.

[0042] Figure 23 This is a SEM image of the tranexamic acid precipitated in Example 23.

[0043] Figure 24 This is a SEM image of 5 g of tranexamic acid precipitated in Example 24.

[0044] Figure 25 This is a SEM image of 10 g of tranexamic acid precipitated in Example 25.

[0045] Figure 26 This is a SEM image of 15 g of tranexamic acid precipitated in Example 26.

[0046] Figure 27 The particle size analysis of tranexamic acid precipitated in Example 21 at a nebulization pressure of 2 bar is shown.

[0047] Figure 28 The SEM analysis of Example 21 after 5 years of environmental storage is shown.

[0048] Figure 29 The particle size analysis of Example 21 after 5 years of environmental storage at a 2 bar atomization pressure is shown.

[0049] Figure 30A and Figure 30B These are the HPLC traces of tranexamic acid (starting material provided as is, Sigma Aldrich, 97% purity) and the tranexamic acid precipitated in Example 21, respectively.

[0050] Figure 31 This is data from the next-generation impactor of Example 21.

[0051] Figure 32 These are representative SEM images of the tranexamic acid precipitated in Examples 25 and 26, respectively.

[0052] Figure 33 These are two representative PXRD spectra of tranexamic acid precipitated in Examples 25 and 26, respectively.

[0053] Figure 34 This is the PXRD spectrum of the tranexamic acid material provided as is.

[0054] Figure 35A SEM images of the powder mixtures from Examples 23 and 24 used for bioavailability studies are shown. Figure 35B The particle size distribution of the powder mixtures in Examples 23 and 24 used for bioavailability studies is shown at an atomization pressure of 2 bar. Figure 35C The PXRD spectra of the powder mixtures from Examples 23 and 24 used for bioavailability studies are shown.

[0055] Figure 36 This shows pharmacokinetic data for the control group (tranexamic acid was administered by gavage at a dose of 60 mg / kg in aqueous solution, which was prepared from a mixture of powders produced in Examples 23 and 24).

[0056] Figure 37 This section shows pharmacokinetic data for the test group (tranexamic acid administered by inhalation at a dose of 8.62 mg / kg, the powder mixture being prepared from the powder produced in Examples 23 and 24).

[0057] Figure 38 shows that, through SEM analysis, Example 26 maintained physical stability after 5 years of environmental storage. Detailed Implementation

[0058] This paper discloses a novel form of tranexamic acid (TXA), its preparation method, and its applications. The inventors were surprised to discover that a dry powder form with desired morphological properties can be prepared using a modified supercritical antisolvent precipitation method. This was previously unknown.

[0059] In the description and claims of this specification, the words “comprising” and “containing” and their variations (e.g., “comprising” and “comprises”) mean “including, but not limited to”, and do not exclude other components, integers, or steps. Furthermore, unless the context otherwise requires, the singular encompasses the plural: in particular, where the indefinite article is used, unless the context otherwise requires, this specification should be understood to consider both the plural and the singular.

[0060] Preferred features of each aspect of the invention may be as described in conjunction with any other aspect. Within the scope of this application, it is expressly intended that the various aspects, embodiments, examples, and alternatives set forth in the foregoing paragraphs, claims, and / or the following description and drawings, particularly their various features, may be employed independently or in any combination. That is, features of all and / or any embodiments may be combined in any manner and / or combination unless these features are incompatible.

[0061] When an upper and lower limit are mentioned for a property, it can also imply the numerical range defined by any combination of the upper and lower limits.

[0062] Unless otherwise stated, references to properties in this specification refer to properties measured at standard temperature and pressure (i.e., atmospheric pressure and a temperature of 20°C).

[0063] All particle sizes (particle diameters) in this article are volume-based, measured, for example by laser diffraction, and include the maximum particle diameter.

[0064] For needle-shaped particles, the average particle length can be determined by scanning electron microscopy (SEM) image analysis. The aspect ratio can also be determined by SEM image analysis.

[0065] Further details regarding the techniques used to determine the nature and features of the invention are provided in the Embodiments section.

[0066] In a first aspect, the present invention provides a composition comprising tranexamic acid particles, wherein the tranexamic acid particles have a D 90The particle size is 5.0 μm or smaller. The composition is preferably a dry powder composition. The tranexamic acid particles are preferably obtained by supercritical antisolvent (SAS) precipitation.

[0067] The composition according to the first aspect surprisingly exhibits a favorable combination of properties, making it an ideal candidate for pharmaceutical formulations, particularly for inhalation administration. These properties include desirable morphology and particle size characteristics (small particle size, narrow unimodal particle size distribution, low aspect ratio), and these properties are present in the original material obtained directly from a supercritical antisolvent precipitation method without further processing (e.g., grinding). The composition also exhibits high crystalline purity and good stability. The composition according to the first aspect is preferably composed of tranexamic acid particles (e.g., crystalline particles).

[0068] While there are several instances of tranexamic acid administered via the respiratory tract, these were primarily for local treatment of pulmonary conditions, mainly pulmonary hemorrhage in children (O'Neil et al., 2020) and hemoptysis (Haghi et al., 2015), and the form of tranexamic acid used was not suitable for effective deposition in the deep lung compartments required for efficient systemic delivery. Lung administration of tranexamic acid for rapid systemic uptake provides the basis for a more widely available drug delivery system for self-administration in non-clinical settings and by patients such as women with postpartum hemorrhage.

[0069] There are many challenges to overcome when considering the preparation of inhalable or blown-in powder formulations containing anti-fibrotic solvents, particularly tranexamic acid. The particles of the drug substance need to be formulated with suitable particle size (typically 1-10 micrometers), morphology, and form for easy atomization when administered from a suitable powder inhaler device. Conventional crystallization / precipitation from organic solvent solutions often yields crystals with irregular shapes, wide particle size distributions, and some particles exceeding 100 micrometers in size, as found with tranexamic acid. Figure 1 As shown, this material is not suitable for effective and efficient drug deposition in the deep alveolar regions of the lungs (target deposition areas for achieving rapid absorption across a large mucosal surface and subsequent systemic drug delivery).

[0070] Other conventional methods for preparing suitable powder formulations involve grinding / micronizing larger crystalline materials. While this method can produce particles within an inhalable range, the ground products are often highly charged and viscous, making secondary processing operations (such as powder flow and mixing) difficult (Hoppentocht et al, 2014). Amorphous regions with varying contents between different batches of material are often formed during grinding, which can lead to moisture sensitivity and post-hygroscopic particle growth. Particle breakage and fracture during grinding, as random events, result in uncontrolled particle size and morphology. Such events can lead to a broad, multimodal size distribution, often causing agglomeration and adhesion of small particles with high surface energy on the surface of larger particles. Furthermore, the particles exhibit irregular, indistinct shapes. These particle aggregates are difficult to atomize and fluidize.

[0071] The composition according to the first aspect has an advantageous morphology and particle shape / size for inhalation / blowing administration. Preferably, in the composition according to the first aspect, the tranexamic acid particles have a D... 10 The particle size is 2.0 μm or smaller, preferably 1.5 μm or smaller, more preferably 1.0 μm or smaller, for example 0.8 μm or smaller, or 0.7 μm or smaller. The D of tranexamic acid particles... 10 Preferably, it is 0.1 μm to 2.0 μm, more preferably 0.2 μm to 1.5 μm, and even more preferably 0.4 μm to 1.0 μm, for example 0.5 μm to 0.8 μm.

[0072] Preferably, in the composition according to the first aspect, the D of the tranexamic acid particles... 50 The particle size is 4.0 μm or smaller, preferably 3.0 μm or smaller, more preferably 2.5 μm or smaller, for example 2.0 μm or smaller. The D of tranexamic acid particles... 50 Preferably, it is 0.5 μm to 4.0 μm, more preferably 1.0 μm to 3.0 μm, and even more preferably 1.5 μm to 2.5 μm, for example 1.5 μm to 2.0 μm.

[0073] In the composition according to the first aspect, the D of tranexamic acid particles 90 The particle size is 5.0 μm or smaller, preferably 4.5 μm or smaller, more preferably 4.0 μm or smaller, for example 3.5 μm or smaller. The D of tranexamic acid particles... 90 Preferably, it is 1.0 μm to 5.0 μm, more preferably 2.0 μm to 5.0 μm, and even more preferably 2.5 μm to 4.5 μm, for example 3.0 μm to 4.0 μm.

[0074] Small particle size, along with a narrow particle size distribution, facilitates nebulization and is therefore advantageous for deep lung delivery via inhalation / blowing. Efficient deep lung delivery is particularly important for effective systemic (rather than local) therapy.

[0075] Preferably, the tranexamic acid particles have a unimodal particle size distribution.

[0076] Preferably, in the composition according to the first aspect, the volume average diameter of the tranexamic acid particles is 4.0 μm or less, more preferably 3.0 μm or less, more preferably 2.5 μm or less, for example 2.0 μm or less. The volume average diameter of the tranexamic acid particles is preferably from 0.5 μm to 4.0 μm, more preferably from 1.0 μm to 3.0 μm, and even more preferably from 1.5 μm to 2.5 μm, for example 1.5 μm to 2.0 μm.

[0077] Preferably, in the composition according to the first aspect, the aspect ratio (e.g., average aspect ratio) of the tranexamic acid particles is 1:1 to 5:1, more preferably 1:1 to 4:1, and even more preferably 1:1 to 3:1. A lower aspect ratio advantageously means that the particles have similar length and width. This provides a preferred shape for delivery of the drug to the lungs by inhalation / blowing. A high aspect ratio (e.g., greater than 1:5) is associated with long, needle-like, needle-like particles that are unsuitable for pulmonary administration.

[0078] In the preferred composition of the first aspect, less than 10% by volume of tranexamic acid particles have a particle size greater than 6 μm. More preferably, less than 8% by volume of tranexamic acid particles have a particle size greater than 6 μm. Even more preferably, less than 5% by volume, or less than 2% by volume (e.g., less than 1% by volume) of tranexamic acid particles have a particle size greater than 6 μm. Preferably, the composition of the first aspect is substantially free of tranexamic acid particles with a particle size greater than 6 μm. A minimum proportion of particles 6 μm or larger is advantageous because particles 6 μm or larger cannot reach the deep lung compartments. Therefore, they cannot effectively deliver the drug systemically via pulmonary mechanisms (e.g., inhalation).

[0079] The composition according to the first aspect is preferably a dry powder composition. In the composition according to the first aspect, the tranexamic acid particles are preferably in crystalline form. The tranexamic acid particles are preferably substantially free of amorphous material. The presence of amorphous material is disadvantageous because amorphous regions tend to be hygroscopic, leading to water-induced bridging and particle growth over time. In the composition according to the first aspect, the tranexamic acid particles preferably contain less than 10% by weight, more preferably less than 5% by weight, and even more preferably less than 1% by weight of amorphous material. Preferably, the tranexamic acid particles are in a substantially pure crystalline form, for example, having a crystallinity of at least 90%, preferably at least 95%, more preferably at least 98%, and even more preferably at least 99%. Purity / crystallinity can be determined, for example, using powder X-ray diffraction, IR / Raman spectroscopy, or HPLC.

[0080] Preferably, in the composition according to the first aspect, the tranexamic acid particles have a unimodal particle size distribution. Advantageously, this provides a uniform powder formulation with a favorable morphology for pulmonary administration.

[0081] In the composition according to the first aspect, advantageously, the tranexamic acid particles are produced directly by a supercritical antisolvent precipitation method, possessing the aforementioned desired morphology and particle characteristics. No additional processing (e.g., grinding or micronization) is required to achieve the desired particle size and morphology characteristics. Therefore, the tranexamic acid particles in the composition according to the first aspect are preferably un-micronized or un-ground. The composition according to the first aspect is preferably un-spray-dried. Methods such as grinding, micronization, and spray drying, particularly when applied to tranexamic acid, tend to produce particles with undesirable properties for inhalation administration, including a broad particle size distribution, a multi-peaked (e.g., bimodal) particle size distribution, charged surfaces causing smaller particles to adhere to larger particles, and inter-particle aggregation. These characteristics significantly hinder drug delivery to deep lung compartments and are therefore ineffective for inhalation administration (especially when systemic treatment is desired).

[0082] The inventors have discovered that the compositions according to the first aspect, once formed, are surprisingly stable under environmental conditions, with no significant changes in particle size characteristics or morphology. This advantageously makes the compositions according to the first aspect highly suitable for pharmaceutical applications where stability and consistency are critical. Storage stability can be determined by assessing the composition (e.g., by HPLC) and / or particle size characteristics (D... 10 D 50 D 90 The change of VMD over time is used for evaluation.

[0083] The composition according to the first aspect preferably showed no chemical degradation as measured by HPLC after 6 months, more preferably 12 months, more preferably 24 months, and even more preferably 48 months under ambient conditions or at 40°C and 75% relative humidity.

[0084] D of tranexamic acid granules 10 Preferably, after 6 months, 12 months, 24 months, and even more preferably 48 months under environmental conditions or at 40°C and 75% relative humidity, the change does not exceed 25%, preferably not more than 20%, more preferably not more than 15%, and even more preferably not more than 10%.

[0085] D of tranexamic acid granules 50 Preferably, after 6 months, 12 months, 24 months, and even more preferably 48 months under environmental conditions or at 40°C and 75% relative humidity, the change does not exceed 30%, preferably not more than 25%, more preferably not more than 20%, and even more preferably not more than 10%.

[0086] D of tranexamic acid granules 90Preferably, after 6 months, 12 months, 24 months, and even more preferably 48 months under environmental conditions or at 40°C and 75% relative humidity, the change does not exceed 30%, preferably not more than 25%, more preferably not more than 20%, and even more preferably not more than 10%.

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

[0088] The aspect ratio of the tranexamic acid particles preferably changes by no more than 30%, no more than 25%, more than 20%, and even more than 10% after 6 months, preferably 12 months, more than 24 months, and even more than 48 months under environmental conditions or at 40°C and 75% relative humidity.

[0089] The composition according to the first aspect advantageously possesses optimal morphology and particle size characteristics for pulmonary delivery, enabling tranexamic acid drugs to be effectively deposited in deep lung compartments, thus allowing for systemic delivery and treatment via inhalation for the first time. The fine particle fraction (FPF) generated during patient inhalation reaches the lungs and produces the necessary therapeutic effect locally, or is delivered systemically via absorption into the bloodstream. Developing a stable dry powder inhalation product that consistently delivers the fine particle fraction throughout its shelf life is a challenge.

[0090] The composition (or tranexamic acid particles of the composition) according to the first aspect preferably exhibits a fine particle fraction of at least 65%, more preferably at least 70%, and even more preferably at least 75%. The fine particle fraction can be determined by a variety of techniques, including glass double impactor (GTI), Anderson cascade impactor (ACI), and next-generation impactor (NGI). Preferably, the fine particle fraction is determined by the next-generation impactor (NGI), for example at a flow rate of 100 liters / minute. The high fine particle fraction provided by the compositions of the present invention advantageously means that a therapeutic payload for systemic treatment can be delivered by inhalation. This is not possible with known tranexamic acid compositions, such as those prepared by spray drying methods.

[0091] The composition according to the first aspect (or the tranexamic acid particles of the composition) preferably exhibits a geometrical standard deviation (GSD) of less than 4 μm, more preferably less than 3 μm, and more preferably less than 2 μm. GSD can be determined by a variety of techniques, including glass double impactor (GTI), Anderson cascade impactor (ACI), and next-generation impactor (NGI). Preferably, GSD is determined by next-generation impactor (NGI), for example at a flow rate of 100 liters / minute.

[0092] In a second aspect, the present invention provides a composition comprising tranexamic acid particles as described above, said tranexamic acid particles being obtained by supercritical antisolvent (SAS) precipitation. Preferred features of the supercritical antisolvent precipitation method are described below with respect to a third aspect.

[0093] In a third aspect, the present invention provides a method for preparing a composition comprising tranexamic acid particles, the method comprising contacting a fluid antisolvent with a solution comprising tranexamic acid in a solvent to precipitate the tranexamic acid particles.

[0094] The inventors have surprisingly discovered that tranexamic acid in particulate form with desired properties can be prepared by using an antisolvent precipitation method. Advantageously, this method allows for the preparation of tranexamic acid compositions with beneficial morphology and high stability. The specific morphology achieved by this method allows for effective pulmonary delivery to deep lung compartments, enabling, for the first time, systemic treatment of various conditions by inhalation / blowing administration of tranexamic acid. Advantageously, the inventors have developed specific methods and conditions to achieve this. Preferably, the method comprises contacting a fluid antisolvent and a solution containing tranexamic acid in the solvent under conditions to precipitate the composition comprising tranexamic acid particles having the properties described above 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) can be tranexamic acid in an amorphous form, tranexamic acid in a crystalline form, or a mixture thereof. The method of the third aspect provides a reliable and reproducible method for preparing an inhalable tranexamic acid particle composition having desired morphological characteristics, regardless of the nature of the tranexamic acid starting material. The conversion of amorphous materials to crystalline materials, and / or the conversion of crystalline materials with undesirable morphologies to easily inhaled formulations, can be achieved. Therefore, the method of the third aspect may further include dissolving the tranexamic acid starting material in a solvent to form a solution containing tranexamic acid in the solvent before contacting the fluid antisolvent with the solution containing tranexamic acid in the solvent. In some embodiments, the tranexamic acid starting material (i.e., before dissolving in the solvent) may have one or more of the following properties:

[0096] - Wide particle size distribution.

[0097] - Amorphous regions.

[0098] - Contains particles with a diameter (maximum size) greater than 20 μm, greater than 50 μm, or greater than 100 μm.

[0099] -D 50 Greater than 20μm, greater than 50μm, or greater than 100μm.

[0100] -D90 Greater than 50μm, greater than 100μm, or greater than 250μm.

[0101] -VMD greater than 20μm, greater than 50μm, or greater than 100μm.

[0102] - Irregular shape.

[0103] - Reunion.

[0104] In the method according to the third aspect, the fluid antisolvent is preferably in the form of a stream. Contacting the fluid antisolvent with the solution of the tranexamic acid compound in the solvent may preferably include: providing a stream of the tranexamic acid solution to a precipitation chamber, providing a stream of the fluid antisolvent to the precipitation chamber, and contacting the stream of the solution with the stream of the fluid antisolvent in the precipitation chamber to precipitate the composition containing tranexamic acid particles in the precipitation chamber.

[0105] The antisolvent can, in principle, be any fluid consistent with achieving the desired particle formation. As is known in the art, the antisolvent used for precipitation is typically chosen such that the product (in this case, a composition containing tranexamic acid particles) is substantially insoluble therein. The role of the antisolvent is to extract the solvent from the tranexamic acid solution and precipitate the desired tranexamic acid particles. Preferably, the fluid antisolvent is carbon dioxide.

[0106] Preferably, the antisolvent is a supercritical fluid, although near-critical fluids may also be suitable in some embodiments. A “supercritical fluid” is a fluid that is simultaneously at or above its critical pressure (Pc) and critical temperature (Tc). In practice, the pressure of a fluid may range from 1.01 to 7.0 times its critical pressure, and its temperature from 1.01 to 4.0 times 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 far exceeding these critical values, such as up to 200 times the relevant critical values. The term “near-critical fluid” encompasses high-pressure liquids (i.e., fluids at or above their critical pressure but below (though preferably close to) their critical temperature) and dense vapors (i.e., fluids at or above their critical temperature but below (though preferably close to) their critical pressure). As an example, the pressure of a high-pressure liquid may be between about 1.01 and 7 times its Pc, and its temperature between about 0.5 and 0.99 times its Tc. Correspondingly, the pressure of dense vapor may be between about 0.5 and 0.99 times its Pc, and the temperature may be between about 1.01 and 4 times its Tc.

[0107] When fluid antisolvents and tranexamic acid solutions come into contact, they can form supercritical or near-critical mixtures.

[0108] The preferred fluid solvent is carbon dioxide, with a pressure less than 200 bar absolute, preferably less than 150 bar absolute. The preferred fluid solvent is carbon dioxide, with a pressure of 50 to 175 bar absolute or 75 to 150 bar absolute. The preferred temperature of the carbon dioxide is 35°C to 80°C or 40°C to 70°C, for example, 50°C to 60°C.

[0109] The density of the fluid antisolvent can be less than 0.80 g / cm³, preferably less than 0.60 g / cm³. The density of the fluid antisolvent can be from 0.20 to 0.80 g / cm³, preferably from 0.25 to 0.70 g / cm³, for example from 0.30 to 0.60 g / cm³.

[0110] Preferably, a highly excess of the antisolvent is contacted with the solution of the tranexamic acid compound. For example, the ratio of the mass fraction of the contacting antisolvent to the mass fraction of the contacting tranexamic acid solution can be 75 or greater, preferably 100 or greater, more preferably 120 or greater. The ratio of the mass fraction of the contacting antisolvent to the mass fraction of the contacting tranexamic acid solution can be from 75 to 300, preferably 80 to 250, more preferably 100 to 200, for example 110 to 175.

[0111] Preferably, the tranexamic acid solution (e.g., a stream of the solution) is contacted with the fluid antisolvent (e.g., a stream of the fluid antisolvent) at a pressure of less than 200 bar absolute, preferably less than 150 bar absolute. Preferably, the tranexamic acid solution (e.g., a stream of the solution) is contacted with the fluid antisolvent (e.g., a stream of the fluid antisolvent) at a pressure of 50 to 175 bar absolute or 75 to 150 bar absolute. Preferably, the tranexamic acid solution (e.g., a stream of the solution) is contacted with the fluid antisolvent (e.g., a stream of the fluid antisolvent) at a temperature of 35°C to 80°C or 40°C to 70°C (e.g., 50°C to 60°C). This can be achieved by maintaining the pressure and temperature within the precipitation chamber at desired levels during the contact between the solution and the antisolvent.

[0112] The antisolvent and tranexamic acid solution can be contacted in any manner consistent with the desired particle formation. Typically, to achieve precipitation, the antisolvent and solution are contacted such that extraction of the solvent system occurs through the action of the antisolvent. Suitablely, this can occur in a precipitation chamber, for example, where temperature and pressure are controlled at desired levels. As is known in the art, mixing energy can be provided by shear between the antisolvent and the solution. Advantageously, the antisolvent and solution can be contacted such that dispersion and extraction of the solvent system occur substantially simultaneously through the action of the antisolvent. Suitablely, the mixing energy can be arranged to provide a nearly instantaneously homogeneous fluid mixture of the antisolvent and the solution.

[0113] The antisolvent stream and the tranexamic acid solution stream can be introduced into the precipitation chamber via their respective channels and outlets, the outlets being arranged relative to each other such that the antisolvent stream introduced through the first channel and the tranexamic acid solution stream introduced through the second channel come into contact with each other in the precipitation chamber.

[0114] The solution stream and the antisolvent stream of the tranexamic acid compound can be supplied to the precipitation chamber at substantially the same point. The solution stream and the antisolvent stream can be co-fed into the precipitation chamber using nozzles with coaxial channels terminating adjacent to each other.

[0115] Preferably, the antisolvent streams (or more than one stream) are arranged to impinge on the solution streams (or more than one stream). This arrangement advantageously provides high shear forces, thereby providing a high degree of contact between the antisolvent and the solution.

[0116] However, any arrangement that provides a good level 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.

[0117] This method may include contacting a relatively high-velocity antisolvent stream with a relatively low-velocity tranexamic acid stream solution. The relative velocities of the two fluid streams can be appropriately managed by varying the diameter and cross-sectional area of ​​the respective injection orifices or nozzles used to deliver the streams and by controlling the flow rate of each fluid stream. For example, the stream velocity can be controlled by an orifice plate of a fixed diameter. This diameter can be arranged to maintain a specific flow rate through the orifice while maintaining a set temperature and pressure upstream of the orifice plate. The resulting stream velocity can be calculated using the density of the fluid upstream of the orifice plate (by reference fluid temperature and pressure), the mass flow rate of the fluid, the cross-sectional area of ​​the orifice, and the pressure difference across the orifice (equations are given in Crystallization process in turbulent supercritical flows, Shekunov, B Yu, Hanna M, York PJ, Crystal Growth, 198-199, 1345-1351 (1999)).

[0118] The amount of kinetic energy suitable for mixing the two fluids and inducing supersaturation varies depending on each solute and solvent mixture used. Preferably, the antisolvent (e.g., CO2) stream velocity is at least 50 m / s, more preferably at least 100 m / s, and even more preferably at least 200 m / s. The antisolvent stream velocity is preferably in the range of 50 to 500 m / s, more preferably 100 to 400 m / s, for example 200 to 300 m / s. The velocity of the tranexamic acid solution is generally lower than that of the antisolvent stream and is not critical to the invention. In one embodiment, the velocity ratio between the antisolvent stream and the solution stream is in the range of 100:1 to 1200:1, preferably 250:1 to 1000:1, for example 350:1 to 600:1.

[0119] Preferably, the flow rate of the antisolvent stream (e.g., CO2) is at least 50 g / min, more preferably at least 100 g / min, and even more preferably at least 150 g / min. The flow rate of the antisolvent stream is preferably in the range of 50 to 500 g / min, more preferably 100 to 400 g / min, for example 150 to 300 g / min.

[0120] In a preferred method, when the fluid antisolvent comes into contact with the tranexamic acid solution, the solvent is extracted from the solution by the fluid antisolvent, forming a mixture of solvent and fluid antisolvent, thereby precipitating the composition containing tranexamic acid particles, for example, in a precipitation chamber. Preferably, the mixture of solvent and fluid antisolvent is removed from the precipitation chamber, for example, through a drain.

[0121] Preferably, the method further includes recovering the composition containing tranexamic acid particles from the settling chamber. This may involve depressurizing the settling chamber and then removing the composition containing tranexamic acid particles from the settling chamber.

[0122] The concentration of tranexamic acid in the solvent can 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 can be 70 mg / ml or less, suitably 20 mg / ml or less. Preferably, the concentration of tranexamic acid in the solvent can be from 5 mg / ml to 200 mg / ml, more preferably from 10 mg / ml to 100 mg / ml, more preferably from 15 mg / ml to 50 mg / ml, for example from 15 mg / ml to 25 mg / ml. The concentration can preferably be based on the volume of the solvent system at standard atmospheric temperature and pressure.

[0123] The solvent preferably comprises an organic solvent. Preferred organic solvents include alcohols, such as C1-C6 alkanols, preferably methanol, ethanol, propanol (e.g., isopropanol (IPA)) or mixtures thereof. Methanol may be particularly preferred. The solvent preferably also comprises an organic acid. Organic acids advantageously increase the solubility of tranexamic acid in organic solvents. Preferred organic acids include acetic acid, formic acid, citric acid, and ascorbic acid, preferably acetic acid (e.g., glacial acetic acid). Preferred solvent systems comprise, or consist of, C1-C3 alkanols (e.g., methanol) and acetic acid, or are composed of C1-C3 alkanols (e.g., methanol) and acetic acid.

[0124] In solvents containing organic solvents and organic acids, the volume ratio of the organic solvent (e.g., C1-C3 alkanols) to the organic acid (e.g., acetic acid) is preferably 50:1 to 1:1, more preferably 20:1 to 2:1, and even more preferably 15:1 to 5:1. In some preferred methods, the solvent may be substantially anhydrous (e.g., it contains no water except for trace amounts present in the organic solvent and / or organic acid).

[0125] The method according to a third aspect of the invention provides a good product mass recovery rate. Preferably, the preparation yield of the composition comprising tranexamic acid particles is at least 25%, more preferably at least 50%, even more preferably at least 60%, and still more preferably at least 75%. Yields up to 100%, such as 50% to 98%, or 70% to 95%, can be advantageously obtained. The yield is based on the percentage of the mass of the recovered tranexamic acid particles relative to the mass of the tranexamic acid starting material.

[0126] The method according to the third aspect of the invention preferably provides a composition comprising tranexamic acid particles directly, which is suitable for inhalation administration without any further processing steps, i.e., it has morphological and particle size characteristics suitable for use as a drug, requiring no further processing of the particles. This does not preclude further steps that do not affect the properties of the tranexamic acid particles (e.g., particle size / morphological characteristics), such as mixing with suitable pharmaceutical excipients or other drugs to provide a pharmaceutical product. Preferably, the method does not include grinding, micronization, or spray drying.

[0127] Preferably, the composition containing tranexamic acid particles prepared by the method of the third aspect can be as described above with respect to the foregoing aspects of the present invention. In particular, the composition containing tranexamic acid particles prepared by this method can preferably contain (or consist of) the composition containing tranexamic acid particles as described above according to the first aspect. Therefore, the preferred features of the composition containing tranexamic acid particles prepared by the method of the third aspect are as described above with respect to the first aspect of the present invention.

[0128] In a fourth aspect, the present invention provides a composition comprising tranexamic acid particles, said composition being obtained by the method according to the third aspect. The preferred features of the method used for the composition according to the fourth aspect are maintained as described above with respect to the third aspect of the invention. The preferred features of the composition according to the fourth aspect are as described above with respect to the first aspect of the invention.

[0129] In a fifth aspect, the present invention provides a pharmaceutical composition comprising (or consisting of) a therapeutically effective amount of the composition comprising tranexamic acid particles according to any one of the first, second and fourth aspects (e.g., the first aspect).

[0130] The pharmaceutical composition is preferably a dry powder composition. However, the pharmaceutical composition may take any suitable form known in the art. Suitablely, tranexamic acid particles may be suspended in a non-solvent carrier.

[0131] The pharmaceutical composition may further comprise suitable excipients. Suitable amounts of excipients are known to those skilled in the art. For example, one or more excipients may be present in an amount of 20% to 99.9% of the total composition weight, preferably 50% to 99% of the total composition weight, suitably 60% to 95% of the total composition weight. Excipients may be of conventional types and can be obtained by any suitable method. An example of a suitable excipient is inhalable lactose.

[0132] However, preferred pharmaceutical compositions do not contain any excipients. Advantageously, the inventors have prepared a form of tranexamic acid that can be used directly as a pharmaceutical composition without excipients. Tranexamic acid particles have an optimal form for use in pharmaceutical compositions, particularly for pulmonary administration (e.g., by inhalation or blowing).

[0133] In a sixth aspect, the present invention provides a composition according to any one of the first, second, fourth, and fifth aspects, which is used as a medicine. This use may preferably involve (e.g., in humans or other mammals, preferably in humans) the prevention or treatment of conditions that are alleviated by inhibiting fibrinolysis.

[0134] In a seventh aspect, the present invention provides a composition according to any one of the first, second, fourth, and fifth aspects for use (e.g., in humans or other mammals, preferably in humans) in the prevention or treatment of blood loss. Blood loss may include internal bleeding and / or external bleeding, and may be chronic or acute.

[0135] In an eighth aspect, the present invention provides the use of the compositions according to any one of the first, second, fourth and fifth aspects for (e.g. in humans or other mammals, preferably in humans) the prevention or treatment of conditions selected from bleeding, trauma, uterine bleeding and bleeding disorders.

[0136] Examples of bleeding include (but are not limited to) postpartum hemorrhage and subarachnoid hemorrhage. Postpartum hemorrhage (PPH) is a particularly preferred condition that can be effectively treated with the compositions described in any of the first, second, fourth, and fifth aspects of this invention. Approximately 14 million cases of postpartum hemorrhage (PPH) occur worldwide each year. PPH is a leading cause of maternal mortality in low-income countries and accounts for nearly a quarter of all maternal deaths globally. Inhalation therapy provides an opportunity for rapid intervention in postpartum hemorrhage events in non-hospital settings. Therefore, this invention provides a simple and potentially more effective alternative to intravenous infusion when on-site personnel are not trained in obtaining intubation access or do not have access to such facilities.

[0137] Examples of trauma include (but are not limited to) traumatic brain injury (including concussion), traumatic bleeding, battlefield trauma, stab wounds, and crush injuries.

[0138] Traumatic brain injury (TBI) is a preferred condition that can be treated with the compositions described in the first, second, fourth, and fifth aspects of this invention. TBI contributes more to global death and disability than any other traumatic injury, affecting 10 million people annually. The CRASH-3 study demonstrated that early intervention with tranexamic acid (within 3 hours) reduces death from brain injury. This invention provides an opportunity to use a safe and easily administered tranexamic acid formulation for this indication. For example, it is conceivable that the compositions of this invention could find practical value in sports injuries (e.g., concussions) through application in on-site interventions and head injury assessment protocols.

[0139] Battlefield trauma is another preferred condition that can be treated with the compositions described in the first, second, fourth, and fifth aspects of this invention. 90% of battlefield trauma deaths occur before the wounded reach a medical facility, and 90% of acute deaths are related to bleeding. It is estimated that 25% of war deaths are medically preventable. Bleeding resulting from battlefield trauma (exceeding 20-30% of blood volume) leads to peripheral circulatory closure, making intravenous access difficult to obtain. Given the challenges of intramuscular injection, the availability of a safe and effective treatment that can be easily administered via pulmonary delivery is clearly both necessary and advantageous. Similar vascular responses occur in different types of severe trauma (e.g., puncture wounds, crush injuries), thus similar benefits can be envisioned.

[0140] Examples of uterine bleeding include (but are not limited to) menorrhagia (excessive menstrual bleeding) and abnormal uterine bleeding. Excessive menstrual bleeding is a preferred condition that can be treated with the compositions described in the first, second, fourth, and fifth aspects of this invention. Currently, tranexamic acid for the treatment of excessive menstrual bleeding is available in oral tablet form. This invention provides an inhalable form of tranexamic acid that can be used to provide rapid onset of action and rapid symptom relief. It can be combined with existing oral therapies for sustained control.

[0141] Examples of bleeding disorders include (but are not limited to) hemophilia and von Willebrand disease.

[0142] In a ninth aspect, the present invention provides a method for treating a ailment in a patient (e.g., a human or other mammal, preferably a human), the method comprising administering to the patient a therapeutically effective amount of the composition according to any one of the first, second, fourth, and fifth aspects. The ailment may suitably be as described above with respect to any one of the sixth to eighth aspects of the invention.

[0143] In the sixth to ninth aspects of the invention described above, the use or treatment preferably comprises administering a therapeutically effective amount of the composition to a patient in need (e.g., a human or other mammal, preferably a human), wherein the administration is via the lungs. Preferably, the administration is by inhalation or blowing, more preferably by inhalation. The administration can be local or systemic, but is preferably systemic. Administration by inhalation can be via a single inhalation or via multiple inhalations (e.g., two or more consecutive breaths). The total amount of the composition administered can preferably be as described below with respect to the tenth aspect of the invention.

[0144] The use or treatment described in the sixth to ninth aspects of the invention may further include administration of tranexamic acid via various routes (e.g., oral or intravenous), for example, after initial pulmonary administration. This use or treatment may further include administration of another drug (e.g., a different antifibrinolytic drug), for example, after the initial administration of tranexamic acid. Advantageously, initial pulmonary administration of tranexamic acid according to the invention can provide rapid symptom relief (e.g., to “buy time”), followed by long-term treatment with another treatment (e.g., oral or intravenous administration of tranexamic acid or another drug).

[0145] The conditions described in aspects six through nine of this invention can be conditions requiring rapid relief (e.g., rapid symptom relief) or rapid onset of action of tranexamic acid. Therefore, the treatment is preferably intended to provide rapid relief (e.g., rapid symptom relief) or rapid onset of action of tranexamic acid within a short time after administration (e.g., less than 20 minutes, or less than 10 minutes, or less than 5 minutes). Rapid relief or rapid onset of action can be defined, for example, as achieving at least 50%, more preferably at least 70%, of peak plasma exposure to tranexamic acid within a relevant time period. Additionally or alternatively, rapid relief or rapid onset of action can 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 disease-related grading system within a relevant time period.

[0146] In a tenth aspect, the present invention provides a composition according to any one 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, such as at least 500 mg, at least 1 g or even at least 2 g.

[0147] In an eleventh aspect, the present invention provides an inhalation or blowing device containing a composition according to any one of the first, second, fourth, and fifth aspects. The device is preferably an inhalation device, such as an inhaler, like a metered-dose inhaler or a dry powder inhaler. More preferably, the device is a dry powder inhaler. The dry powder inhaler may have a capsule containing a composition according to any one of the first, second, fourth, and fifth aspects. The inhalation or blowing device (e.g., a dry powder inhaler) can be a single-dose device or a multi-dose device. Preferably, the device is a multi-dose dry powder inhaler, such as a respiratory-driven multi-dose dry powder inhaler, such as Orbital. TM Inhaler.

[0148] Example

[0149] For all embodiments, the starting material used was tranexamic acid (97% purity) obtained from Sigma Aldrich. Acetic acid was commercially available glacial acetic acid.

[0150] Particle size analysis was performed using a Sympatec HELOS / KF analyzer equipped with a RODOS dry powder disperser (with an ASPIROS micro-dosing unit). The measurement range was 0.2 to 87.5 µm.

[0151] Aspect ratios (range and average) were measured from SEM images. More than 100 particles were measured in each case.

[0152] Examples 1 to 4 Comparative Examples (Conventional Crystallization and Grinding / Micronization)

[0153] Example 1

[0154] Figure 1 The image shows a SEM (HIROX SH4000M scanning electron microscope and SEC MCP-100P ion beam sputtering coating system) of tranexamic acid starting material (97% purity) obtained from Sigma Aldrich. The starting material exhibits a wide range of particle sizes, with the largest size greater than 100 μm. The particles are irregular in morphology and show signs of aggregation, with smaller particles adhering to the surface of larger particles. Formal particle size analysis could not be performed because the particle size of the sample was too large for the instrument's range (0.2 to 87.5 µm), meaning that accurate particle size parameters (D) could not be obtained. 10 D 50 D 90 The results were obtained from VMD (Vibration Dynamics Determination) measurements. The aspect ratio ranged from 1:1 to 1:12, with an average aspect ratio of 1:5. Particle sizes up to 1200 µm in length were observed. These characteristics indicate that it is impossible to use this material without modification when formulating powder products for inhaled drug delivery.

[0155] Example 2

[0156] Figure 2 SEM images show tranexamic acid powder prepared by conventional solvent evaporation crystallization at ambient temperature from a tranexamic acid solution dissolved in methanol:acetic acid (9:1 v / v). Large particles were observed, with particle characteristics similar to the starting material obtained from Sigma-Aldrich. Formal particle size analysis could not be performed because the particle size of the sample was too large for the instrument's range (0.2 to 87.5 µm), meaning that accurate particle size parameters (D) could not be obtained. 10 D 50 D 90 VMD (Vibration Dynamics Determination) measurement results. Aspect ratios ranged from 1:1 to 1:16, with an average aspect ratio of 1:7. Particle sizes up to 1500 µm were observed.

[0157] Example 3

[0158] Tranexamic acid samples were subjected to air jet milling using a Food Pharma Systems Labo Mill (serial number FP3241) at a pressure of 2 bar. Although inhalable particles were produced, SEM ( Figure 3 The results show that the powder from the high-energy milling process consists of particles of irregular shape and size, due to uncontrolled particle breakage and fragmentation. Smaller particles adhere to the surface of larger particles, and there are signs of agglomeration. The powder also exhibits electrostatic charge, leading to viscous flow behavior.

[0159] The sample shows D 10 It is 0.9 µm, D 50It is 2.4 µm, D 90 The particle size was 5.9 µm, and the VMD was 3.0 µm. 8% by volume of particles showed a particle size greater than 6 µm. The aspect ratio ranged from 1:1 to 1:9, with an average aspect ratio of 1:5. Particles with a maximum length of 30 µm were observed.

[0160] Example 4

[0161] Figure 4 The particle size distribution of the powder prepared in Example 3 is shown (Sympatec Helos equipped with a RODOS dry powder disperser, atomization pressure 2 bar). This milled tranexamic acid sample showed a wide size distribution and a relatively high percentage (20%) of particles larger than 5 micrometers, confirming that powders prepared using a milling process are not suitable for delivering high particle deposition when administered via the pulmonary route.

[0162]

[0163] D 50 D 90 Sympatec Helos with VMD * equipped with RODOS dry powder disperser, atomization pressure 2 bar, n=3

[0164] Examples 5 to 26

[0165] The purpose of the experiment was to use supercritical antisolvent (SAS) precipitation to form tranexamic acid particles that are easy to inhale or blow into.

[0166] The method used to generate inhalable tranexamic acid particles is the SAS (supercritical antisolvent) method.

[0167] In this method, the antisolvent and drug (in this case, tranexamic acid) solutions are continuously introduced into a pressurized precipitation vessel (also called a precipitation chamber) through their respective channels. The flow rate of each feed line (typically carbon dioxide as the antisolvent and a solution of the drug in an organic solvent) is monitored. The pressure in the precipitation vessel is controlled and maintained by a back pressure regulator that runs in a single outlet discharge channel from the precipitation vessel. The temperature of the entire assembly is controlled, typically using an oven in laboratory and small-scale operations. In this way, supercritical or near-critical antisolvent fluid conditions are created within the precipitation vessel.

[0168] The outlets of the two feed lines enter the settling vessel at substantially the same point, where the antisolvent and solution meet. To achieve a high degree of contact, mixing, and dispersion between the antisolvent and solution, a nozzle arrangement with coaxial channels terminating adjacent to each other is used, for example, to co-feed the antisolvent and solution into the settling vessel. Alternatively, one or more antisolvent streams can be arranged to impinge on the solution streams to provide a high degree of contact, mixing, and dispersion between the antisolvent and solution. Other contact, mixing, and dispersion arrangements are known, and examples of suitable equipment are particularly from WO95 / 01221, WO96 / 00610, WO98 / 36825, WO-99 / 44733, WO99 / 59710, WO01 / 03821, and WO008082, which are incorporated herein by reference.

[0169] After contact, mixing, and dispersion of the antisolvent and solution under supercritical or near-critical antisolvent fluid conditions, the solvent in the solution is extracted and dissolved by the supercritical or near-supercritical fluid, thereby forming a supercritical solution or a near-critical antisolvent solution, respectively. This supercritical or near-critical antisolvent solution is discharged from the precipitation container through a discharge line. After solvent extraction, the drug particles precipitate and remain in the precipitation container and are collected, typically in a collection device such as a basket. The precipitated particle powder is then recovered after depressurization in the precipitation container.

[0170] For each embodiment, tranexamic acid is dissolved in an organic solvent mixture containing an organic acid.

[0171] As described above, a stream of tranexamic acid solution is contacted with a stream of supercritical or near-critical carbon dioxide in a precipitation chamber to form tranexamic acid particles.

[0172] In Examples 5 through 26, the effects of a series of particle formation conditions on particle precipitation were examined, in which the particle formation conditions were modified.

[0173] The altered particle formation conditions and particle characterization results are listed in Table 1. More specifically, Table 1 covers the following particle formation conditions / results:

[0174] - The volume of the sedimentation chamber (“chamber volume”) is expressed in milliliters (ml).

[0175] - Types of mixed nozzle arrangements (“nozzle types”) – In the first type of nozzle arrangement (Type I), carbon dioxide is arranged to impinge on the solution to provide high shear force, while in the second type of nozzle arrangement, carbon dioxide and solution are co-fed into the settling chamber through nozzles having coaxial channels that terminate adjacent to each other to provide lower shear force. The first type of nozzle arrangement has a carbon dioxide orifice diameter of 750 micrometers (Type II), and the second type of nozzle arrangement has a carbon dioxide orifice diameter of 500 micrometers (Type III).

[0176] - The concentration of tranexamic acid in the organic solution (“drug solution concentration”) is expressed in milligrams (mg / ml) per milliliter of organic solvent mixture.

[0177] - Temperature of the carbon dioxide stream ("CO2 T"), expressed in degrees Celsius (°C).

[0178] - The environmental pressure of carbon dioxide streams (“CO2 p”), expressed in bar.

[0179] - The density of the carbon dioxide stream (“CO2 density”) is expressed in grams per cubic centimeter (g / cm³).

[0180] - The flow rate of tranexamic acid solution into the precipitation chamber (“Drug Solution Flow Rate”) is expressed in grams per minute (g / min).

[0181] - The flow rate of carbon dioxide entering the precipitation chamber (“CO2 flow rate”) is expressed in grams per minute (g / min).

[0182] - The velocity of the carbon dioxide stream entering the precipitation chamber (“CO2 velocity”) is expressed in meters per second (m / s).

[0183] - The ratio of the mass fraction of the carbon dioxide flow entering the precipitation chamber (CO2 flow rate / [CO2 flow rate + drug solution flow rate]) to the mass fraction of the tranexamic acid solution flow entering the precipitation chamber (drug solution flow rate / [CO2 flow rate + drug solution flow rate]) (“mass fraction to flow rate”), dimensionless.

[0184] - The cumulative particle diameter distribution of precipitated tranexamic acid particles reaching 50% by volume, i.e., 50% by volume of particles having a diameter less than this value, and 50% by volume of particles having a diameter greater than this value (“D”). 50 ”, expressed in micrometers (µm).

[0185] - The cumulative particle diameter distribution of precipitated tranexamic acid particles reaching 90% by volume, i.e., 90% by volume of particles having a diameter less than this value, and 10% by volume of particles having a diameter greater than this value (“D”). 90 ”, expressed in micrometers (µm).

[0186] - The volume average diameter (“VMD”) of the precipitated tranexamic acid particles, expressed in micrometers (µm).

[0187] Table 1

[0188]

[0189] Table 1 (continued)

[0190]

[0191] D 50 D 90 Sympatec Helos with VMD* equipped with RODOS dry powder disperser, atomization pressure 2 bar

[0192] Initial tranexamic acid experiments from SAS yielded a variety of morphologies. These included "needle-like" (acupuncture-like), flaky, spherulitic, lamellar, spherical, and plate-like forms. Under some experimental conditions, aggregates (fused particles) and agglomerates (mixtures of two or more particle morphologies) were produced. Controlling particle morphology is crucial for the precipitation of aspirable or blown-in particles and for achieving homogeneous particles, particularly D... 50 and D 90 Challenges were presented for particles with percentiles between 1 and 4 µm and between 2 and 10 µm, respectively, and with a volume average diameter of 1–4 µm.

[0193] Examples 5-19 produced fine powders, but with uncontrolled particle habits and / or particle size distributions exceeding the range required for powder delivery to the lungs. Observed shapes included flakes (Example 18 – see...). Figure 18 ), spherulites (Example 7 – see Figure 7 ) and plate-like (Example 21 – see Figure 21 )form.

[0194] Under certain process conditions, undesirable aggregates (mixtures of two or more particulate forms) are produced, for example, in Example 5 ( Figure 5 Showing a mixture of "needle-like" (needle-shaped), spherulites, and spherical particles) and Example 16 ( Figure 16 The mixture of lath-like and spherulite particles is shown, as well as agglomerates (fused particles), such as in Example 12 (see Example 12). Figure 12 Alternative nozzle configurations did not produce acceptable powder (Examples 17 and 18).

[0195] Example 21

[0196] For Example 21, it was surprisingly found that a fine, free-flowing powder with controlled particle size distribution and morphology was obtained. SEM examination of the particles from Example 21 revealed uniform, smooth-surfaced crystalline particles with a plate-like morphology. Figure 21 (and narrow particle size distribution. It is noteworthy that these particles possess...) Figure 3 The grinding particles have different shapes and there is no agglomeration seen in the ground particles.

[0197] With ground materials (see) Figure 4 Compared to [previous material], this material has a more regular particle size distribution and a narrower particle size range (see [reference]). Figure 27 All particles exhibit distinct primary particle characteristics, with no "smaller" particles adhering to the surface of other particles, reflecting an improved and smoother surface morphology, which is beneficial for particle atomization. There is no inter-particle aggregation.

[0198] The particle size of the particles from Example 21 was analyzed using a Sympatec Helos laser diffraction particle size analyzer equipped with a RODOS dry powder disperser and an atomization pressure of 2 bar. Figure 27 The data in the table below shows that particles with a narrow particle size distribution and an inhalable size were produced.

[0199]

[0200] D 50 D 90 Sympatec Helos with VMD * equipped with RODOS dry powder disperser, atomization pressure 2 bar, n=3

[0201] The aspect ratio ranges from 1:1 to 1:4, with an average aspect ratio of 1:2.

[0202] The powder sample from Example 21 was stored under ambient conditions in a sealed 20 ml glass screw-cap scintillation vial and found to be physically stable after 5 years. Figure 28 SEM analysis in the sample confirmed that the particle morphology and size distribution of the stored powder were similar to those of the "originally prepared" sample (see [reference]). Figure 21 Similar to [other organisms], there were no signs of solvent bridging or growth. Figure 29 The data presented in the table below confirms that no particle growth or aggregation occurred during the 5-year storage period (comparatively). Figure 27 ).

[0203]

[0204] D 50 D 90 Sympatec Helos with VMD * equipped with RODOS dry powder disperser, atomization pressure 2 bar, n=3

[0205] The chemical purity of the powder in Example 21 was assessed by high-performance liquid chromatography (HPLC) using an Agilent 1100 series HPLC system equipped with a UV-Vis detector (220 nm). The HPLC method used conformed to Ph Eur monograph 0875. (Column: ODS (C18) 250 × 4.6 mm, 5 µm, 80 Å pore size, with pre-column protection; mobile phase consisted of 11 g anhydrous sodium dihydrogen phosphate, 5 mL triethylamine, and 1.4 g sodium dodecyl sulfate in 500 mL deionized water, pH adjusted to 2.5 with o-phosphoric acid, and brought to a final volume of 600 mL with deionized water, followed by the addition of 400 mL methanol and mixing; flow rate 0.9 mL / min, injection volume 20 µL). At the same solution concentration as the calibration sample (prepared from tranexamic acid material (97% purity) provided as is), the purity of the processed material in Example 21 indicates that SAS processing did not degrade the obtained tranexamic acid (similar retention time and area at similar solution concentrations) (see Figures 30a and 30b).

[0206] By examining the scaled-up experimental space of the SAS process based on Experiment 21, it was surprisingly found that fine, free-flowing powders with controlled particle size distribution and morphology were obtained for Experiments 22-26. Furthermore, these examples demonstrated the production of inhalable or blown-in tranexamic acid particles, particularly D... 50 and D 90 Particles with percentiles between 1 and 4 µm and 2 and 10 µm, respectively, and a volume average diameter of 1.7 µm to 2.0 µm. The process conditions for Examples 22-26 were determined as follows:

[0207] - The mass fraction of the contacting carbon dioxide to the mass fraction of the contacting tranexamic acid solution is 120 or greater, and the density of the carbon dioxide is between 0.40 and 0.55 g / cm³. 3 Within the range.

[0208] - The ratio of the mass fraction of carbon dioxide in contact to the mass fraction of the tranexamic acid solution in contact is 120 or greater.

[0209] Surprisingly, at higher carbon dioxide flow rates (a carbon dioxide mass fraction to tranexamic acid mass fraction ratio of 120 or greater), inhalable particles could be produced at temperatures of 50°C and 60°C, pressures of 110 bar and 125 bar, and a solution flow rate of 1.64 g / ml. Furthermore, at lower carbon dioxide flow rates, a carbon dioxide mass fraction to tranexamic acid solution mass fraction ratio greater than 80 surprisingly led to favorable particle formation.

[0210] Examples 25 and 26 show favorable plate-like particles and particle size distribution (see Figure 25 and 26Optimal scale-up process conditions show that favorable particle characteristics such as particle morphology and particle size distribution are maintained as batch size increases.

[0211] Examples 24 (5 g batch), 25 (10 g batch), and 26 (see...) Figure 24 , 25 (26) shows that the powder from the optimal process conditions at the pilot plant scale exhibits good reproducibility between samples. The particles demonstrate D... 50 (1.59-1.87 µm) and D 90 (3.15-3.59 µm) values ​​and controlled uniform plate-like morphology, which are consistent with the data from small-scale production of Example 21 (Example 21-D). 50 2.04 µm and D 90 Similar to 4.90 µm.

[0212] The representativeness of the chemical and solid-state properties of the scaled-up powder samples was assessed by powder X-ray diffraction (PXRD, Rigaku MiniFlex 600 powder X-ray diffractometer, scan range 3°–40°, step size 0.020°, scan rate 2° / min, 40 kV, 15 mV). Tranexamic acid has only one known polymorphic form (Traxidot Public assessment report – scientific discussion, DK / H / 2590 / 001 / MR, January 31, 2017). Figure 33 Two representative PXRD spectra of the precipitated tranexamic acid from Examples 25 and 26 are shown.

[0213] The powder in Example 26 was found to be physically stable after 5 years of storage in a 20 ml glass screw-cap scintillation vial at room temperature, see [link to example]. Figure 38A and 38B . Figure 38B It shows the morphology and particle size distribution and Figure 38B (SEM analysis after preparation in Example 30) showed similar results, with no signs of solvent bridging or particle growth.

[0214] Although particle size analysis was not performed on Example 20, SEM images ( Figure 20 This indicates that the sample has similar desired morphology, shape, and particle size characteristics to Examples 21 to 26.

[0215] The yield of Example 21 (small-scale) was 66%. The yields of Examples 22 to 26 (pilot plant scale) ranged from 61% to 88%.

[0216] Examples 20 through 26 demonstrate that conditions have been developed that surprisingly provide tranexamic acid particles with a favorable combination of particle characteristics (morphology / shape and particle size distribution) for delivery to deep lung compartments. Without being bound by theory, it is believed that the combination of solvent system and CO2 velocity contributes to the desired characteristics.

[0217] Example 27 – Bioavailability Study

[0218] Two 5-gram samples from Examples 23 and 24 were blended for 10 minutes using a Turbula® mixer (Willy A. Bachofen AG, Germany). Prior to dispensing, the blended powders were analyzed and characterized by SEM, PSA analysis (n=6) using Sympatec at 2 bar atomization pressure with an R1 range (0.18–35 µm), and PXRD analysis, as detailed below. Figure 35A , 35B And 35C. From Figure 35B It can be seen that no particles with a diameter greater than 6 µm were displayed.

[0219] Eight male Dawkley rats, with a mean weight of 200 g, were randomly divided into two groups of four (experimental group – inhalation, control group – oral). The oral dose (60 mg / kg) was calculated based on the clinical adult oral dose. 10 ml of a 6 mg / ml tranexamic acid aqueous solution was administered via gastric tube. The inhalation dose was calculated based on the actual aerosol atomization concentration delivered to the rat exposure chamber (8.62 mg / kg). Powder aerosol was generated from a mixed powder bed using compressed air. The resulting aerosol cloud was circulated into a rotary exposure chamber, where restricted rats were allowed to inhale the powder aerosol for 10 minutes.

[0220] Blood samples were collected from the control (oral) group at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. For the experimental (inhalation) group, blood samples were collected at the following time points: immediately after administration (10 minutes), and at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration.

[0221] Compared to the slower systemic absorption following oral administration, aerosol administration produces a rapid increase in tranexamic acid plasma levels. Figure 36 and 37 Data showed that systemic uptake following powdered aerosol administration was rapid, reaching a peak level of up to 58% at the first measurable time point after the end of exposure (10 minutes). The mean time to peak concentration was 1.1 hours (SD 0.77) for powdered aerosol administration, compared to 2.0 hours for oral administration. Figure 36The pharmacokinetic data for the control group (administered by gavage at a dose of 60 mg / kg) are shown. Figure 37 The pharmacokinetic data for the experimental group (inhaled administration at a dose of 8.62 mg / kg) are shown. The relative bioavailability of the aerosol inhalation group relative to the oral administration group was 138%. These findings suggest that aerosol drug delivery via the respiratory route provides rapid systemic uptake and improved bioavailability of tranexamic acid compared to oral administration.

[0222] Example 28 – Next Generation Impactor (NGI) Research

[0223] Aerodynamic particle size distribution (APSD) has been identified as a critical quality attribute (CQA) for oral inhaled and nasal pharmaceutical products (OINDPS). APSD defines the behavior of particles in a moving airflow and is relevant to understanding potential lung deposition and thus potential drug efficacy. NGI is a high-performance, precision cascade impactor ideal for testing at all relevant flow rates specified in the relevant pharmacopoeia.

[0224] Drug particles between 5 and 10 µm typically deposit in the upper respiratory tract, particles between 0.5 and 5 µm settle in the deep lungs, while particles <0.5 µm undergo Brownian motion and are likely to be exhaled by the patient. The larger the GSD (Gross Dispersion Size), the more sites the aerosol deposits in the respiratory tract. Ideally, the aerosol's GSD should be <2 µm and as close to monodisperse as possible to increase deposition at the desired site of action, thereby improving therapeutic efficacy.

[0225] Next-Generation Impactor (NGI) studies were conducted on the atomization behavior of Example 21. These studies specifically determined the total emission dose (TED), fine particle dose (FPD), fraction of fine particles in TED (FPF%), median mass aerodynamic diameter (MMAD), and geometric standard deviation (GSD) of pure SAS tranexamic acid. The aerodynamic particle size distribution of Example 21 was determined using NGI. Figure 31 (Table 2).

[0226] For NGI studies, 8 mg of the powder from Example 21 was directly weighed into Qualicaps-V No. 3. ® -1 capsule, and with high-resistance Plastiape RS-01 TM The apparatus was delivered, and two copies of Example 21 were analyzed. Each plate was quantitatively washed with deionized water and transferred to a volumetric flask of known volume, which was then brought to the mark with deionized water. The sample was then analyzed by the HPLC method described above.

[0227] Table 2. NGI Operating Conditions and Results

[0228]

[0229] The data provided in Table 2 shows good FPD and FPF. High FPF (see Table 2). Figure 31 The values ​​of 0.5 μm and GSD <2 µm indicate good potential for lung deposition and rapid onset of action. MMAD is closely correlated with the preliminary particle size data (unimodal particle size distribution, VMD = 2.0 µm) of Example 27 generated on a Sympatec Helos equipped with a RODOS dry powder disperser. Results of the bioavailability study (see...) Figure 37 This demonstrates the potential for excellent APSD and rapid onset of action.

[0230] References

[0231]

Claims

1. A composition comprising tranexamic acid particles, wherein the tranexamic acid particles have a D... 90 It is 5.0µm or smaller.

2. The composition according to claim 1, wherein the tranexamic acid particles can be obtained by supercritical antisolvent (SAS) precipitation.

3. The composition according to claim 1 or 2, wherein the tranexamic acid particles have one or more of the following particle size characteristics: i. D 10 The range is from 0.1 µm to 2.0 µm; ii. D 50 The range is from 1.0 µm to 3.0 µm; iii. D 90 The range is from 2.0 µm to 5.0 µm; and iv. The aspect ratio is 1:1 to 5:

1.

4. The composition according to any one of the preceding claims, wherein the tranexamic acid particles have a unimodal particle size distribution.

5. The composition according to any one of the preceding claims, wherein less than 10% by volume of the tranexamic acid particles have a particle size greater than 6µm.

6. The composition according to any one of the preceding claims, wherein the tranexamic acid particles are in crystalline form.

7. The composition according to any one of the preceding claims, wherein the tranexamic acid particles are substantially free of amorphous material.

8. The composition according to any one of the preceding claims, wherein the tranexamic acid particles are not ground, micronized, or spray-dried.

9. A method for preparing a composition comprising tranexamic acid particles, the method comprising contacting a fluid antisolvent with a solution comprising tranexamic acid in a solvent to precipitate the tranexamic acid particles.

10. The method of claim 9, wherein the antisolvent is a supercritical fluid.

11. The method according to claim 9 or 10, wherein the antisolvent is carbon dioxide, preferably with a pressure in the range of 75 to 150 bar absolute pressure and a temperature in the range of 35 to 80°C.

12. The method according to any one of claims 9 to 11, wherein the antisolvent is in the form of a stream, and the velocity of the antisolvent stream is at least 50 m / s.

13. The method according to any one of claims 9 to 12, wherein one or more streams of the antisolvent are arranged to impinge on the solution.

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

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

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

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

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

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

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

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

22. The composition for use according to claim 21, wherein the condition is postpartum hemorrhage, trauma selected from traumatic brain injury and battlefield trauma, or excessive menstrual bleeding.

23. The composition for use according to claim 21, wherein the disease is postpartum hemorrhage.

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

25. An inhalation or inhalation device having a composition according to any one of claims 1 to 8, 17 and 18.

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