Crystalline pharmaceutical composition comprising sugar and lipid complex particles for

Abstract

Pharmaceutical compositions comprising composite particles having a controlled aerodynamic particle size distribution wherein the composite particles comprise one or more active pharmaceutical ingredients (APIs), at least one sugar and at least one lipid are described. The method of preparing the pharmaceutical composition comprises the steps of: a. Mixing API and one or more excipients into a homogeneous powder, the excipients comprising at least one sugar or at least one lipid, or both at least one sugar and at least one lipid; and b, reducing the particle size distribution of the mixture. The micronized pharmaceutical compositions allow for delivery of crystalline, stable APIs that have better aerodynamic properties than micronized APIs alone, as well as improved downstream processing and stability properties.

Description

[0001] Technical Field of the Invention

[0002] The present invention generally relates to the field of dry powder drugs, and more particularly to pharmaceutical compositions of particles, especially composite particles, which have enhanced aerodynamic properties for inhalation delivery.

[0003] One of the main advantages of pulmonary drug delivery is the rapid onset of clinical effect, which is due to the large lung surface area (>100 m 2 )), combined with a high blood perfusion rate (flow rate up to 5.7 L / min) and a thin absorption membrane (0.1 - 0.2 μm) [1]. In addition, delivering drugs to the lungs enables avoidance of first-pass metabolism, increased bioavailability, and reduced required dosage, thus reducing the treatment cost. Pulmonary drug administration has been used for low-dose delivery for many years to treat conditions such as asthma. High-dose delivery by inhalation is interesting because many new drugs show low bioavailability when administered orally due to low solubility or absorption. In addition, for local delivery, pulmonary delivery shows reduced systemic side effects and higher concentration at the site of action, while for systemic delivery, it improves the administration of unstable molecules in a non-invasive manner.

[0004] Pressurized metered-dose inhalers, nebulizers, and dry powder inhalers (DPIs) are common devices for delivering drugs to the lungs. Among them, the latter has the advantages of being propellant-free, not requiring coordinated actuation with inhalation, being portable and relatively inexpensive, and keeping the drug in a solid state, which may provide higher physicochemical stability [2].

[0005] Inhaled powders need to be within a specific particle size distribution (PSD) range (50% of the particles by volume (Dv50) should be below 5 μm) and have a mass median aerodynamic diameter (MMAD) of 1 to 5 μm in order to target the deep respiratory tract. To improve stability, powders that are fully crystalline and moisture-free are preferred.

[0006] The performance of DPI formulations is usually evaluated by the emitted dose (ED) and the fine particle dose (FPD). The emitted dose refers to the mass of powder (mg / capsule) that leaves the capsule upon actuation per capsule, and the fine particle dose refers to the mass of powder (mg / capsule) that passes through a cut-off aerodynamic diameter of 5 μm upon actuation per capsule. The fine particle fraction (FPF) is another performance indicator, obtained by dividing the FPD by the ED or the labeled declared mass. All measurements of these performance indicators should show a relative standard deviation (RSD) of less than 5%.

[0007] The powder flow properties depend on the particle size distribution, which presents the main drawback of the pulmonary drug delivery route, i.e., the need to reduce the particle size to target deeper airways. The performance of fine powders is affected by the particle size because as the particle diameter decreases, the relative importance of the interparticle forces to gravity increases: while gravity is proportional to the cube of the particle size, the van der Waals force is directly proportional to the particle size, so after size reduction, the latter becomes relevant. In addition, electrostatic forces, capillary forces, and mechanical interlock are other relevant interparticle interactions, which also depend on the particle size and shape, as well as surface texture and contact area, surface energy, hygroscopicity, and relative humidity [2]. The particle shape can limit the approach of two particles, thus reducing the interparticle interactions. The same effect is also produced by surface roughness: in fact, surface asperities on the order of 1 μm limit the van der Waals force to negligible values [3]; the opposite is true when the particles are planar or elongated because close contact is allowed. If the size of the asperities is large enough that the entrapment of other particles may occur, mechanical interlock and non-uniform distribution of surface energy will occur. Relative humidity plays a role in two opposite mechanisms because it increases the interactions caused by capillary forces (which can be as strong as for more hygroscopic materials), but also increases the conductivity, thus dissipating the static charge. During powder mixing and other processing, collisions and friction between particles generate charges [2]. Generally speaking, the van der Waals force is the main one, and all these interactions are only relevant to particles with diameters in the order of a few micrometers or less, so these particles are more prone to cohesion and agglomeration.

[0008] When delivering low doses, the most common strategy to ensure acceptable atomization and handle the inherent cohesion of fine powders is to use a coarser inert carrier, such as lactose, which dissociates after inhalation and remains in or deposits in the oral / upper respiratory tract, enabling the drug particles to redisperse in the air stream. For high-dose formulations (usually with API < 5 mg delivered), using a carrier is not appropriate because the saturation of the active sites of the carrier leads to undesirable particle separation. Another approach is to produce carrier-free soft aggregates of the API, which remain intact during processing but are easily de-agglomerated after inhalation. However, the inherent cohesion of fine powders poses great variability to the carrier-free method because stable agglomerates may form, which do not de-agglomerate during actuation and thus do not reach the lower respiratory tract, significantly reducing the actual delivered dose [4].

[0009] Co-milling represents the co-processing of two or more types of particles (e.g., API and lubricants) for the production of performance-enhanced composite particles. The benefits obtained are usually due to the dispersion of additive particles on the surface of API particles. Additionally, co-milling can be used to enhance the absorption of poorly soluble drugs, such as itraconazole mentioned previously, by providing composite particles with increased wettability [5]. The excipients used in co-milling include many different types of compounds, which will act through different mechanisms

[10] [9].

[0010] The observed improvement in the aerodynamic performance of co-milled formulations has been explained by the adhesion of excipient particles to the high surface energy sites of API particles [6], which act as spacers, reducing the contact area and hindering interparticle interactions. In some cases, excipient particles may orient their hydrophobic groups towards the outside and sometimes form a coating film [7]. Generally, studies have explained the improvement in FPF through the reduction of surface energy [8][9]. Electrostatic stabilization has also been reported as a mechanism for preventing particle agglomeration through repulsion between particles, providing long-term particle size stability

[10] .

[0011] In terms of preventing solid state transformations and crystal defects that often occur during milling, co-milling has shown promising results

[11]

[12] . Mechanically induced amorphization competes with thermodynamically induced recrystallization. Therefore, generally, milling below the glass transition temperature of the material is likely to produce amorphous products, as it provides conditions for the retention of the amorphous state after the induction of shear disorder effects. On the other hand, using co-milling technology to reduce the overall glass transition temperature of the drug composition, the efficiency of recrystallization is an order of magnitude, and no amorphization is observed. Crystalline formulations are desirable because the amorphous state is inherently unstable, leading to recrystallization, which promotes the formation of solid bridges and subsequent agglomeration. Additionally, the amorphous state is more prone to water absorption and requires more stringent storage conditions. Moreover, controlling the crystalline state of the API can lead to controlled release by avoiding supersaturation of the amorphous form in the lung lining fluid and thus can be used for therapeutic effects. This is one of the main advantages of the milling process compared to spray drying, which is known to produce amorphous products.

[0012] Stability is a key property of drug powders. Particle size increase due to cohesion, water absorption due to amorphous regions, subsequent solid bridge formation, or drug degradation are all undesirable effects. As mentioned previously, co-milling may be a promising method for improving the stability of pharmaceutical products, as it can be used to seek to minimize these effects. Additionally, some excipients can form hydrophobic coating films to prevent moisture absorption and degradation [7].

[0013] Since smaller particles have a larger surface area, they dissolve faster, and reducing particle size alone becomes a promising method to enhance dissolution. Using a wetting agent in co-grinding for this purpose may be an improved method by adding a substance that reduces the surface tension of water, making it easier to spread onto the surface. When these particles are prone to dissolution, the composite particles may become porous API particles, thus further increasing the contact area.

[0014] US8802149B2 relates to a method for preparing a pharmaceutical composition for inhalation by spray drying, which contains an active ingredient, a hydrophilic compound, and a hydrophobic compound. The literature has studied spray-dried formulations containing hydrophilic and hydrophobic materials

[15]

[16] . However, in contrast to, for example, jet-milling, it is known that this method produces completely amorphous products, which are more prone to water absorption and stability problems, which may be crucial in inhalation formulations because the size of the particles / aggregates determines the delivered dose. In addition, compared with most grinding processes, spray drying is a more complex process, involving the optimization of several steps (dissolution, atomization, and collection) and the use of solvents.

[0015] US8182838B2 describes a method of jet-milling active particles in the presence of amino acids, metal stearates, and / or phospholipid particles to form composite active particles, and also includes mixing carrier particles with the composite active particles. However, as mentioned above, the carrier-based method is not suitable for high doses. In addition, the safety of amino acids for pulmonary delivery has not been recognized, and the hydrophobicity of metal stearates and phospholipids may be unfavorable for dissolution, and their prolonged residence time in the airway can cause irritation, especially for metal stearates. US8932635B2 describes the surface coating of magnesium stearate on active particles for inhalation delivery, aiming to delay dissolution.

[0016] EP1663155B1 describes a co-jet-milling method for preparing composite particles for pulmonary delivery, and the excipients include amino acids, metal stearates, or phospholipids that coat the active particles. These materials have the above-mentioned disadvantages.

[0017] US11103448B2 describes a method of separately grinding metal stearate particles and active material particles, and jet-milling the previously ground active particles and metal stearate particles to produce composite particles for inhalation. The disadvantages of this method are that it includes several steps and has the hydrophobicity and airway irritation of the above-mentioned metal stearates.

[0018] Lo et al. prepared carrier-based particles for inhalation with enhanced properties by spray-drying liposomes of API particles together with sugars (sucrose, trehalose, and lactose) and lipids (DMPC, DPPC, DSPC, or DPPG) with stabilizing functions

[13] . As previously mentioned, the carrier-based method is not suitable for high doses. In addition, the process involves several steps.

[0019] US2007178166 describes a method for preparing a dry powder pharmaceutical formulation for pulmonary or nasal administration. API particles are mixed with a first excipient to form a first powder mixture, which is then milled, and subsequently, in a second step, the milled mixture is mixed with a second excipient to form a mixed dry powder. The particles of the second excipient are larger than the microparticles or nanoparticles in the milled mixture.

[0020] WO2022126105A1 discloses methods, compositions, and kits for treating fibrotic lung diseases. The method utilizes a combination product for inhalation, which comprises a dry powder formulation provided in an inhaler and is administered by oral inhalation. The composition comprises diketopiperazine particles, and the dry powder of the drug is prepared by spray-drying.

[0021] CN106102748A discloses a dry powder formulation comprising acetylsalicylic acid particles and includes milling and spray-drying steps.

[0022] US2006257491A1 describes mechanical fusion and jet milling for preparing dry powder for pulmonary inhalation. The mixture comprises API and additive materials such as amino acids / metal stearates / phospholipids. The formulation comprises leucine (an amino acid) or magnesium stearate (a metal stearate), and due to the hydrophobicity of the compounds, they may pose safety issues for pulmonary delivery or irritation, respectively.

[0023] KR20190068591 describes dry particles comprising crystalline particulate antifungal agents and focuses on preparing crystalline drugs treated with an anti-solvent and a stabilizer to form a suspension. There is no disclosure of milling a mixture of different components to improve aerodynamic performance and / or stability. Summary of the Invention

[0024] In a broad aspect, the present invention provides a pharmaceutical composition comprising one or more active pharmaceutical ingredients (API), at least one sugar, and at least one lipid. Due to the preparation method, the composition has a controlled aerodynamic particle size distribution. The API is in crystalline form. Suitably, other components of the composition may also be in crystalline form. For example, either or both of the sugar and lipid components may be in crystalline form.

[0025] Suitably, the composition comprises composite particles. Such particles contain the active ingredient and at least two excipients in a single particle. Preferred particles are composite particles comprising an API, a sugar component, and a lipid component. The composition is preferably prepared by co-grinding.

[0026] In another aspect, the present invention thus provides a pharmaceutical composition comprising composite particles, wherein the composite particles comprise one or more crystalline forms of an active pharmaceutical ingredient (API), at least one sugar, and at least one lipid. The particles have a controlled aerodynamic particle size distribution. Thus, one aspect of the present invention is composite particles prepared by co-grinding, wherein the composite particles comprise one or more active pharmaceutical ingredients (API), at least one sugar, and at least one lipid. Thus, co-ground composite particles are provided, which comprise one or more active pharmaceutical ingredients (API), at least one sugar, and at least one lipid. Thus, in one aspect, the present invention provides crystalline composite particles.

[0027] Suitably, co-grinding is used to obtain the particles of the composition. For example, co-grinding has been reported as the co-processing of API / excipients with additive materials for the preparation of composite particles (e.g., see

[18] Lau et al., 2017). Thus, the co-ground particles are one aspect of the present invention. Thus, one aspect of the present invention is to co-grind an API, a sugar (e.g., mannitol), and a lipid (e.g., cholesterol) together to provide composite particles. Such particles are preferably crystalline.

[0028] The present invention also provides a pharmaceutical composition as disclosed and claimed herein for use as a medicament. For example, the pharmaceutical composition can be used to treat a pulmonary disorder in a patient.

[0029] Those skilled in the art will understand that, for example, the compositions of the present disclosure can be used in dry powder inhalers. Any suitable dry powder inhaler can be used. Thus, the present invention also provides a dry powder inhaler comprising a pharmaceutical composition as disclosed and claimed herein.

[0030] In another aspect, a method for preparing a pharmaceutical composition as disclosed and claimed herein is also provided, the method comprising the following steps:

[0031] a. Mixing an API and one or more excipients into a homogeneous powder, the excipients comprising at least one sugar or at least one lipid, or both at least one sugar and at least one lipid;

[0032] b. Reducing the particle size distribution of the mixture.

[0033] In a preferred aspect, step (b) is carried out without using a solvent.

[0034] Step (b) preferably comprises co-grinding of the particles. It also preferably comprises jet milling, but other similar methods can also be used if desired. For example, co-grinding can be carried out by wet milling. As described below, for example, high-pressure homogenization can be a useful method in the context of the present invention.

[0035] The present invention also provides composite particles having a controlled aerodynamic particle size distribution when prepared by the method of the present invention. The composite particles comprise one or more active pharmaceutical ingredients (APIs), at least one sugar, and at least one lipid. A pharmaceutical composition comprising such composite particles is also provided. Suitably, the components of the composition are crystalline.

[0036] Accordingly, the present invention relates to a pharmaceutical composition of composite particles for an inhalation preparation, the composite particles comprising at least one API, at least one sugar, and at least one lipid, prepared by co-grinding, having improved properties by hindering particle-particle interactions and preventing cohesion. We have found that the performance enhancement obtained by using the pharmaceutical composition is reflected in better stability, reduced amorphization, and improved dissolution, all of which require only minimal amounts of added materials. Sugars have been widely used as carriers in DPIs and are known for improving wettability. However, surprisingly, we have found that sugars are able to improve the FPF of co-ground formulations when added in very small amounts. In addition, compared to other hydrophilic compounds, sugars have the following benefits: providing a taste that increases patient compliance and having known biocompatibility due to their use as carriers for several decades compared to other materials such as polymers or amino acids for which toxicological studies of the lungs are not extensive. The inclusion of sugars in inhalation preparations reduces cohesion by attaching to the API and acting as an inert spacer between the drug particles. Lipids account for 90% of the surfactants present in the lungs and are composed of 40 wt% DPPC and smaller amounts of other lecithins and cholesterol, which makes these substances generally recognized as safe substances (GRAS) [7]. These compounds protect the drug from moisture and improve atomization due to their anti-adhesive properties. Cholesterol is a biocompatible material that has been shown to reduce particle aggregation and provide the above benefits by coating the drug [7]

[14] . The low melting points of these compounds hinder their application in techniques such as spray drying. However, when combined with sugars in a dry co-grinding process, surprisingly, these compounds have been shown to be suitable for providing improved aerodynamic properties (fine particle fraction and emitted dose) and enhanced stability to the particles while reducing the fouling effect throughout the process.

[0037] The pharmaceutical composition of the present invention comprises crystalline composite particles prepared by co-grinding API with sugar and lipid. Due to the use of a wetting agent (sugar) and a biocompatible and biodegradable substance (lipid) naturally present in the lung, it simultaneously hinders the particle-particle interactions that lead to aggregation, has enhanced performance and stability, and does not hinder dissolution. The particles described in the present invention for improving aerodynamic performance are different from the particles described in the prior art that contain amino acids, metal stearates or phospholipids, because we believe that this improvement does not come from the anti-adhesion properties of the excipients, but from the ability of sugarfine to adhere to the API active sites and prevent aggregation by acting as a spacer. The particles described in the present invention also have the additional benefit of improving patient compliance through taste.

[0038] Summary of the Drawings

[0039] Figure 1 shows the particle size distribution determined by laser diffraction at 5 bar in the experiment of Example 1.

[0040] Figure 2 shows the scanning electron micrograph of the co-grinding experiment of Example 1

[0041] Figure 3 shows the XRPD diffraction pattern of the experiment of Example 2.

[0042] Figure 4 Show the XRPD diffraction pattern of the experiment of Example 4.

[0043] Figure 5 Show the aerodynamic characteristics of the experiment of Example 4 using the Plastiape device.

[0044] Figure 6 Show the dissolution curve of Example 1.

[0045] The pharmaceutical composition of the present invention preferably comprises composite particles having a particle size distribution suitable for inhalation. For example, the particle size distribution can be such that Dv90 is less than or equal to 20 μm. Dv90 is a point in the particle size distribution at which 90% of the total volume of the material in the sample is "covered" and included. In a preferred aspect, the Dv90 of the particle size distribution is less than or equal to 10 μm.

[0046] In one aspect, the pharmaceutical composition according to the present invention can have a particle size distribution in which the range is about 0.1 μm ≤ Dv90 ≤ 6 μm.

[0047] It has been found that when used, for example, in a typical dry powder inhaler, the compositions of the present invention generally have a greater emitted dose (ED) than other types of compositions, such as those that are otherwise similar or identical but contain only the API or contain the API and only one excipient. Accordingly, the present invention also provides a pharmaceutical composition as described above, wherein the emitted dose obtained, for example, as measured by a dose unit sampling apparatus (DUSA), or a fast screening impactor (FSI) or a next generation impactor (NGI), is higher than the emitted dose of a pharmaceutical composition containing only the API when the compositions are prepared under the same conditions.

[0048] It has also been found that when used, for example, in a typical dry powder inhaler, the compositions of the present invention generally have a greater fine particle fraction (FPF) than other types of compositions, such as those that are otherwise similar or identical but contain only the API or contain the API and only one excipient. Accordingly, the present invention also provides a pharmaceutical composition as described above, wherein the fine particle fraction (FPF) obtained, for example, as measured by DUSA, or FSI or NGI, is higher than the fine particle fraction of a pharmaceutical composition containing only the API when the compositions are prepared under the same conditions.

[0049] It has also been found that the compositions of the present invention have excellent dissolution properties, which are generally better than the dissolution properties of other types of compositions, such as those that are otherwise similar or identical but contain only the API or contain the API and only one excipient. Accordingly, the present invention also provides a pharmaceutical composition as described above, wherein the dissolution time of the pharmaceutical composition is reduced compared to a composition that is identical in all other respects but contains only micronized API.

[0050] It has also been found that the compositions of the present invention have good physical stability and / or chemical stability, which is generally superior to the physical stability and / or chemical stability of other types of compositions, such as those that are otherwise similar or identical but contain only the API or contain the API and only one excipient. Accordingly, the present invention also provides a pharmaceutical composition as described above, wherein the physical stability and / or chemical stability of the pharmaceutical composition is increased compared to a composition containing only micronized API.

[0051] Any pharmaceutically acceptable sugar can be used in the compositions of the present invention, but particularly those sugars suitable for use in human patients by the inhalation route. One sugar, or a combination of two or more sugars, can be used, but a single sugar is preferably used. Preferably, the sugar is selected from the group consisting of mannitol, trehalose, trehalose hydrate, sucrose, lactose or raffinose, or a combination of two or more of them.

[0052] In one aspect, a pharmaceutical composition is preferred, wherein the composite particles contain a sugar, and the sugar is mannitol or trehalose, or a combination thereof. Mannitol is a particularly preferred sugar. For example, we have found that mannitol is superior to other sugars approved for inhalation due to its lower hygroscopicity and non-toxicity. Mannitol is also capable of providing fine particles of a high dose of integrated drug upon powder atomization.

[0053] Any pharmaceutically acceptable lipid can be used in the compositions of the present invention, but particularly those lipids suitable for use in human patients via the inhalation route. One lipid can be used, or a combination of two or more lipids, but a single lipid is preferably used. Preferably, the lipid is selected from the group consisting of: saturated or unsaturated fatty acids; glycerides, including neutral glycerides or phosphoglycerides; non-glyceride lipids, such as steroids, waxes or sphingolipids; or a combination of two or more of them.

[0054] In one aspect of the present invention, the lipid is selected from the group consisting of: steroids, and the steroids are selected from the following steroid classes: cholestanes, cholanes, pregnanes, androstanes or estranes; or phosphoglycerides, and the phosphoglycerides are selected from the group consisting of: phosphatidylcholine, phosphatidylglycerol or phosphatidylethanolamine, or a combination of two or more of them.

[0055] In a preferred aspect, the lipid is selected from steroids, particularly cholestanes, such as cholesterol. In a further preferred aspect, the lipid is selected from phosphoglycerides or phospholipids, particularly lipids such as dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC) or lecithin, or a combination of two or more of them. Cholesterol and DSPC are two particularly preferred lipids. For example, cholesterol is the major neutral lipid component found in pulmonary surfactant, and we have found that it provides particularly good results when combined with a sugar component (such as those disclosed herein, including mannitol).

[0056] In one aspect, a pharmaceutical composition is preferred, wherein the composite particles contain mannitol or trehalose as the sugar and cholesterol as the lipid.

[0057] The pharmaceutical composition according to the present invention contains a balanced ratio of the respective components to provide the desired effect. Preferably, the respective components of the composition are present as follows, where the weight % of the components is expressed based on the weight of the total composition.

[0058] The API component is preferably present in an amount of 50% to 99.5% by weight, more preferably in the range of 80% to 99.5% by weight, depending on the API. A range of 90% to 95% by weight can also be used.

[0059] The sugar component is preferably present in an amount of 0.5% to 45% by weight, more preferably in the range of 0.5% to 20% by weight, depending on the sugar. For good results, a preferred sugar such as mannitol can be used, and its amount used is, for example, 5% to 20% by weight, especially 10% or more, for example 10% to 20% by weight.

[0060] The lipid component is preferably present in an amount of 0.01% to 5% by weight, more preferably in the range of 0.04% to 2% by weight, depending on the lipid. For good results, a preferred lipid such as cholesterol can be used, and its amount used is, for example, 0.04% to 2% by weight.

[0061] Thus, in a broad aspect, a preferred pharmaceutical composition according to the present invention is one in which, based on the weight of the total composition, the weight percentages of the components are as follows: API is 50% to 99.5% by weight; sugar is 0.5% to 45% by weight; and lipid is 0.01% to 5% by weight.

[0062] A further preferred pharmaceutical composition of the present invention is one in which, based on the weight of the total composition, the weight percentages of the components are as follows: API is 80% to 99.5% by weight; sugar is 0.5% to 20% by weight; and lipid is 0.04% to 2% by weight.

[0063] Some preferred example compositions are shown in Table 1 below:

[0064]

[0065] Table 1. Examples of compositions according to the present invention (ITZ = itraconazole; IVM = ivermectin; REM = remdesivir)

[0066] Some preferred API:sugar:lipid weight ratios are from 89:10:1 to 90:5:5. Examples include 89:10:1, 94:5:1, and 90:5:5. Among these ratios, a particularly preferred sugar is mannitol, and particularly preferred lipids include cholesterol or DSPC.

[0067] In one aspect, the API is present in an amount of 30% or more by weight based on the weight of the total composition, or preferably in an amount of 50% or more by weight based on the weight of the total composition.

[0068] The API itself can in principle be any API suitable for administration using a powder formulation, in particular an API suitable for administration via the pulmonary route. For example, the API can be an antifungal agent such as itraconazole; an antiparasitic drug such as ivermectin; or an antiviral drug such as remdesivir.

[0069] The present invention is capable of providing high doses of the API, particularly via the inhalation route. Thus, the present invention provides the pharmaceutical composition as described, wherein the composition is a high-dose inhalation composition, wherein a single inhalation dose provides at least 2.5 mg or more of the API, such as greater than 5 mg or more. A high dose can also mean that the amount of the API in the inhaled drug dose is higher than 4% by weight of the dose (see, for example,

[20] Sibum et al., 2018; Adhikari et al., 2022).

[0070] Regarding the inhaler, different types of inhalers can be used with the composition of the present invention, but a dry powder inhaler is preferred and can be, for example, a single-use inhaler. Preferably, the dry powder inhaler includes a mouthpiece, an inhaler body, and a cartridge for receiving the dose, which is understandable. In a preferred aspect, the cartridge is movable relative to the inhaler body to provide the dose through the mouthpiece. The dry powder inhaler employed can include one such that the inhaler cartridge includes a reservoir or a plurality of reservoirs. In a preferred aspect, each reservoir of the inhaler cartridge provides a single dose.

[0071] As described above, broadly speaking, the method according to the present invention includes the following steps:

[0072] a. Mixing the API and one or more excipients into a homogeneous powder, the excipients comprising at least one sugar or at least one lipid, or both at least one sugar and at least one lipid;

[0073] b. Reducing the particle size distribution of the mixture.

[0074] Thus, in one aspect, step (a) can include mixing the API and the sugar, followed by step (b) for the mixture of the API and the sugar. In this case, the method would include a further step (c), wherein the mixture of the API and the sugar that has undergone step (b) is further mixed with a lipid component, and then the resulting mixture is subjected to a second step (b) - that is, reducing the particle size distribution of the mixture of the API and the sugar and the lipid components. In a preferred aspect, step (c) is a co-grinding step, such as co-grinding the API with the sugar and the lipid by jet milling. Thus, the method of the present invention always includes at least one step, preferably a co-grinding step, wherein at least one sugar and at least one lipid are subjected to a step of reducing the particle size distribution of the mixture together with the API.

[0075] Thus, in the method of the invention disclosed and claimed herein, in a preferred aspect, the method may comprise first mixing the API and at least one sugar and co-grinding them together, for example by jet milling, and then mixing at least one lipid with the resulting pharmaceutical composition and jet milling to obtain a pharmaceutical composition comprising the API, at least one sugar and at least one lipid.

[0076] Thus, if desired, the method of the invention includes the possibility of two co-grinding steps. A first co-grinding step of the API with a separate sugar component (or a separate lipid component), and, optionally, a second co-grinding step in which the mixture of the API and the sugar component (or the mixture of the API and the lipid component) is co-ground with the second component not yet present (i.e., the lipid component or the sugar component).

[0077] Thus, one feature of the invention is to perform step (b) with two excipient components (i.e., sugar and lipid) and the API, preferably by co-grinding. This is preferably done by jet milling. This helps to provide improved aerodynamic performance. Another preferred feature of the method is that no second mixing step is required after the co-grinding of the API, sugar and lipid.

[0078] Step (a) of the method may comprise mixing the API with the at least one sugar and the at least one lipid simultaneously, or may comprise sequential mixing of the at least one sugar and the at least one lipid. That is, the mixing of the sugar and lipid components may be carried out one after another. The order of mixing is not critical, so for sequential mixing, the sugar or the lipid may first be mixed with the API, followed by the second component.

[0079] The injection pressure in the jet milling step may preferably be, for example, from about 2 bar to about 12 bar. In one aspect, the injection pressure is from about 4 bar to about 8 bar.

[0080] The temperature at which the size reduction step (step (b)) is carried out is preferably about 60 °C or lower.

[0081] In some aspects, the temperature at which the size reduction step (step (b)) is carried out is about 10 °C or lower. For example, this step may be carried out as a cryogenic jet milling step, i.e., jet milling is carried out under cold conditions, mainly to avoid formation of the amorphous form.

[0082] In other aspects, the temperature at which the size reduction step (step (b)) is carried out is about 20 °C or higher. Thus, temperatures from 20 °C to 60 °C are generally suitable.

[0083] In the method of the present invention, an advantage is that the conditioning step can be omitted. In a typical conditioning step, the formulations are stored under controlled temperature and relative humidity conditions during their preparation. Thus, in a preferred aspect, the methods disclosed and claimed herein include those in which no conditioning step is employed to prepare the final ready-to-use formulation, or in which a reduced amount of conditioning time is employed as compared to the conditioning time required to condition a composition containing only micronized API. Detailed Description

[0084] In one embodiment, the present invention can be carried out by mixing pre-screened (600 μm) API particles with, for example, pre-screened mannitol particles and cholesterol particles in a low-shear mixer at, for example, 96 rpm for 10 minutes. For example, the resulting composition is milled in a vertical jet mill using compressed nitrogen to produce, for example, a milling pressure of 6 bar and a Venturi pressure of 7 bar, and the composition is fed to the jet milling device at, for example, 40 g / h. The jet mill is the simplest dry size reduction device, including a milling chamber (usually a flat disk with milling nozzles), where the feedstock is fed through a Venturi tube, and compressed gas (usually air or nitrogen) is used to generate injection pressure and milling pressure through the nozzles, creating a vortex that promotes particle-particle and particle-wall collisions, which result in breakage and subsequent size reduction. The resulting particle size distribution is controlled by varying the applied milling pressure or the solid flow rate, and the Venturi pressure is typically defined as 1 bar higher to prevent backflow. For example, 20 mg to 50 mg of the resulting composition is filled into, for example, size 3 HPMC capsules, and the capsules can be driven using a DPI device.

[0085] Depending on the target respiratory region, different aerodynamic particle sizes can be prepared. Different particle sizes can be obtained by varying the specific energy used during milling. Co-jet milling carried out at a milling pressure of 2 - 6 bar results in a reduction of the particle size distribution of some API to inhalable sizes, but harder API requires a pressure of 6 - 12 bar. The temperature at which the process is carried out affects the mobility of the particles, and thus the brittleness and extensibility range of the material. For some materials, co-milling may need to be carried out at a temperature of 0 - 20 °C to provide sufficient brittleness. For other materials, co-milling at a temperature of 20 - 60 °C is required for adhesion of the additive particles to the active agent particles to occur. When needed, co-milling can also be carried out using a wet method (e.g., high-pressure homogenization). For example, in contrast to jet milling, which does not control particle shape, this method is capable of providing round particles and also produces a narrower particle size distribution. It has been reported that co-milling with certain excipients at a weight percentage of 0.5% significantly improves aerodynamic performance [9]. On the other hand, when dealing with certain active agent particles, an amount of additive up to 20% is beneficial.

[0086] The formulations in the embodiments of the present invention are processed using the following devices:

[0087] 1) Turbula (Willy A. Bachofen AG, Basel, Switzerland) low-shear mixing device.

[0088] 2) Laboratory-scale jet mill MCOne (Jetpharma Solutions SA, Ballena, Switzerland).

[0089] Except for cholesterol, all materials are manually sieved according to the sizes specified in each embodiment. Mixing and grinding conditions are also specified in each embodiment, which are based on the applicant's previous grinding experiments.

[0090] The formulations in the embodiments of the present invention contain one or more of the following materials:

[0091] ● Lactose Respitose SV003 from DFE Pharma, Germany

[0092] · Mannitol Pearlitol from Roquet, USA

[0093] · Trehalose dihydrate from Sigma Aldrich, USA

[0094] · Cholesterol from Sigma Aldrich, USA

[0095] · Itraconazole from Fagron Iberica, Spain

[0096] · Ivermectin from Hovione PharmaScience, Portugal

[0097] ● Remdesivir from Hangzhou MolCore BioPharmatech Co., Ltd

[0098] The formulations in the embodiments of the present invention are characterized by the following techniques:

[0099] ● Helos laser diffraction instrument combined with Rodos dry dispersion unit and Aspiros module (Sympatec GmbH, Germany) is used for the determination of particle size distribution of most formulations. Dispersion pressures of 0.1 bar (using R2 lens (0.45 - 87.5 μm), focal length 50 mm) and 5 bar (using R1 lens (0.18 - 35 μm), focal length 20 mm) are applied respectively to determine the size of aggregates or single particles. The speed is maintained at 50 mm / s. All determinations are carried out in duplicate.

[0100] ● All in vitro aerosolization studies were performed using hydroxypropyl methylcellulose (HPMC) capsule size 3 (Capsugel, Colmar, France) containing 30 mg ± 1.5 mg of powder. All were tested by performing two actuations of the same capsule in a Fast Screening Impinger (FSI) (Copley Scientific, Nottingham, UK) with 15 ml of dissolution medium added to the pre-separator which was connected to a vacuum pump (Copley Scientific, Nottingham, UK) at a flow rate of 60 L / min or 100 L / min. The emitted dose (ED) was quantified gravimetrically by weighing the inhaler device and the capsule before and after actuation, and the fine particle dose (FPD) was determined gravimetrically by weighing the filter before and after actuation. The cutoff size of the pre-separator was 5 μm, so the fraction of the labeled mass (fine particle dose) reaching the filter was the fine particle fraction (FPF). The ED included all API outside the inhaler device. Some formulations were characterized in a Next Generation Impinger (NGI) (Copley Scientific, Nottingham, UK) which had a pre-separator connected to a vacuum pump (Copley Scientific, Nottingham, UK). The NGI cups were coated with 1 mL of a 1% glycerol ethanol (v / v) solution. 15 ml of dissolution medium was placed in the pre-separator. Each test consisted of actuating the capsule once into the NGI using a DPI device at 60 L / min or 100 L / min for 4 s or 2.4 s respectively. The tests were performed in triplicate. The API content deposited at each stage was recovered and analyzed by HPLC to enable determination of the ED and FPD and the distribution between stages, ensuring a mass balance of the recovered material with an error of less than 15%. All aerodynamic performance experiments were performed in triplicate.

[0101] ● X-ray powder diffraction (XRPD) patterns were obtained using a PANalytical (Malvern, UK) X’Pert PRO X-ray diffractometer with Cu K radiation (λ = 1.54 Å). The generator voltage and current intensity were set at 45 kV and 40 mA respectively, the 2θ scan range was from 4° to 40°, the step size was 0.0131303°, and the counting time per step was 99.450 s. Samples were loaded using zero background technology.

[0102] Example 1 - Co-grinding of Itraconazole with Sugar and Lipid

[0103] Trials 1, 2, 3, 4, and 5 were prepared by low shear mixing and jet milling.

[0104] Experiment 1: Mannitol was pre-screened through a 600 μm sieve and mixed with cholesterol in a low-shear mixer at 96 rpm for 10 minutes. The previous mixture was mixed with itraconazole pre-screened through a 600 μm sieve in a low-shear mixer at 96 rpm for 10 minutes. The ternary mixture was fed into a laboratory-scale vertical jet mill and placed under the conditions described in Table 1.2.

[0105] Experiment 2: Mannitol pre-screened through a 600 μm sieve was mixed with itraconazole pre-screened through a 600 μm sieve in a low-shear mixer at 96 rpm for 10 minutes. The mixture was fed into a laboratory-scale vertical jet mill and placed under the conditions described in Table 1.2.

[0106] Experiment 3: (Only API): Itraconazole was screened through a 600 μm sieve, fed into a laboratory-scale vertical jet mill, and placed under the conditions described in Table 1.2.

[0107] Experiment 4: Trehalose dihydrate was pre-screened through a 600 μm sieve and mixed with cholesterol in a low-shear mixer at 96 rpm for 10 minutes. The previous mixture was mixed with itraconazole pre-screened through a 600 μm sieve in a low-shear mixer at 96 r / min for 10 minutes. The ternary mixture was fed into a laboratory-scale vertical jet mill and placed under the conditions described in Table 1.2.

[0108] Experiment 5: Mannitol was pre-screened through a 600 μm sieve and mixed with cholesterol in a low-shear mixer at 96 rpm for 10 minutes. The previous mixture was mixed with itraconazole pre-screened through a 600 μm sieve in a low-shear mixer at 96 rpm for 10 minutes. The ternary mixture was fed into a laboratory-scale vertical jet mill and placed under the conditions described in Table 1.2.

[0109] Table 1.2 - Summary of process parameters and formulation composition for Example 1.

[0110]

[0111] The particle size distribution of the micronized materials was characterized by laser diffraction, the crystalline state was characterized by XRPD, and the morphology was characterized by SEM - summarized in Table 2, "Error! Reference source not found" and "Error! Reference source not found".

[0112] All experiments showed particle sizes within the inhalable range. "Error! Reference source not found".A (particle size distribution of Experiment 3) and "Error! Reference source not found".B (particle size distribution of Experiment 5) showed only one (similar) particle population, indicating the formation of composite particles, or that the API and excipients were micronized to a similar extent.

[0113] The XRPD presented by the milled material is the same as that of only the API (Test 3) or has one of the diffraction peaks of mannitol (Tests 1, 2, and 5) or trehalose dihydrate (Test 4), indicating that the solid state of the material has not changed.

[0114] SEM micrographs of Test 3 (only API) and Test 5 (material co-milled with mannitol and cholesterol) show that the presence of excipients has no significant effect on the particle morphology.

[0115] Table 2 - Characterization of the micronized mixtures of Example 1.

[0116]

[0117] After micronization, the powders obtained from each test were filled into HPMC No. 3 capsules at 20 - 25 °C and a relative humidity of 50 ± 10% with a filling weight of 30 mg. Each capsule was driven using a Plastiape inhaler (flow rate of 100 L / min, pressure drop of 4 kPa).

[0118] Table 3 summarizes the characterization of the aerodynamic performance of the prepared capsules by FSI.

[0119] The results of Tests 1, 2, and 3 show that the fine particle fraction increased from 39.9 ± 0.1% of the emitted dose of only the API (Test 3) to 50 ± 1.2% of the emitted dose of Test 2 containing API and mannitol, and to 59.4 ± 0.9% of the emitted dose of Test 1 containing API, mannitol, and cholesterol. These results demonstrate that the drug composition containing sugar and cholesterol prepared by co-milling significantly improves the aerodynamic performance compared to co-milling only with sugar. The results of Tests 3, 4, and 5 show that the fine particle fraction (FPF) increased from 39.9 ± 0.1% of the emitted dose of only the API (Test 3) to 55.7 ± 0.5% of the emitted dose of Test 4 containing API, trehalose dihydrate, and cholesterol, and to 56.5 ± 1.1% of the emitted dose of Experiment 5 containing API, mannitol, and cholesterol.

[0120] These results indicate that the improvement obtained with the drug composition containing sugar and cholesterol prepared by co-milling, with different weight percentage ranges of excipients (0.5 wt% excipient in Test 4, 5 wt% excipient in Test 1, 10.3 wt% excipient in Test 5), improves the aerodynamic performance.

[0121] Table 3 - Summary of the capsule characterization of Example 1.

[0122]

[0123] Example 2 - Ivermectin co-milled with sugar and lipid

[0124] Trials 2 and 3 were prepared by low-shear mixing and jet milling.

[0125] Trial 1 (API only): Ivermectin was sieved through a 600-μm sieve and fed into a laboratory-scale vertical jet mill and placed under the conditions described in Table 4.

[0126] Trial 2: Mannitol was pre-sieved through a 600-μm sieve and mixed with cholesterol in a low-shear mixer at 96 rpm for 10 minutes. The previous mixture was then mixed with ivermectin pre-sieved through a 600-μm sieve in a low-shear mixer at 96 rpm for 10 minutes. The ternary mixture was fed into a laboratory-scale vertical jet mill and placed under the conditions described in Table 4.

[0127] Trial 3: Mannitol was pre-sieved through a 600-μm sieve and mixed with cholesterol in a low-shear mixer at 96 rpm for 10 minutes. The previous mixture was then mixed with ivermectin pre-sieved through a 600-μm sieve in a low-shear mixer at 96 rpm for 10 minutes. The ternary mixture was fed into a laboratory-scale vertical jet mill and placed under the conditions described in Table 4.

[0128] Table 4 - Summary of process parameters and formulation composition for Example 2.

[0129]

[0130] The particle size distribution of the micronized materials was characterized by laser diffraction, and their crystalline state was characterized by XRPD - summarized in Table 5 and "Error! Reference source not found". All trials showed particle sizes within the inhalable range, and Trial 3 (lower API content, higher mannitol and cholesterol content) showed smaller particle sizes. These results suggest that the presence of these two excipients may contribute to particle breakage and thus result in a smaller PSD for similar micronization energy. The milled materials presented XRPD identical to the diffraction peaks of the API, or Trials 2 and 3 with mannitol, indicating that the API and excipients are crystalline after micronization.

[0131] Table 5 - Characterization of micronized mixture products for Example 2.

[0132]

[0133] After micronization, the powders obtained in Trials 1, 2, and 3 were manually filled into HPMC size 3 capsules at 20 - 25 °C and 50 ± 10% relative humidity, with a target fill weight of 30 mg, and driven using a Plastiape inhaler (flow rate of 100 L / min, pressure drop of 4 kPa) to evaluate aerodynamic performance.

[0134] The fine particle fraction (determined by gravimetric analysis FSI) of the filled capsules was 14.1 ± 2.1% of the delivered dose for API only, and 31.6 ± 0.5% and 41.9 ± 1.4% of the delivered dose for Test 2 and Test 3 containing API, mannitol, and cholesterol at 9.4% and 20.0% by weight, respectively - see Table 6. The results indicate that the drug compositions containing sugar and cholesterol prepared by co-grinding have beneficial effects on the aerodynamic performance of high-dose ivermectin formulations in terms of delivered dose and fine particle dose. As more excipients are added, the effect increases continuously, resulting in an almost three-fold increase in FPF compared to the formulation ground without excipients.

[0135] Table 6 - Summary of capsule characterization for Example 2.

[0136] Test 1 Test 2 Test 3 Filling Weight (mg) 30.0±1.5 30.0±1.5 30.0±1.5 FPD (mg powder / capsule) 5.5±0.1 9.1±0.1 12.2±0.4 ED (mg powder / capsule) 26.4±1.9 28.9±0.8 29.1±0.1 FPF (Percentage of ED) 14.1±2.1 31.6±0.5 41.9±1.4

[0137] Example 3 - Modulating Co-Ground High-Dose Formulations of Itraconazole

[0138] Tests 2 and 3 were prepared by low-shear mixing and jet milling.

[0139] Test 1 (API only): Itraconazole was sieved through a 600 μm sieve and fed into a laboratory-scale vertical jet mill and placed under the conditions described in Table 7.

[0140] Test 2: Trehalose dihydrate was pre-sieved through a 600 μm sieve and mixed with cholesterol in a low-shear mixer at 96 rpm for 10 minutes. The previous mixture was mixed with itraconazole pre-sieved through a 600 μm sieve in a low-shear mixer at 96 rpm for 10 minutes. The ternary mixture was fed into a laboratory-scale vertical jet mill and placed under the conditions described in Table 7.

[0141] Test 3: Mannitol was pre-sieved through a 600 μm sieve and mixed with cholesterol in a low-shear mixer at 96 rpm for 10 minutes. The previous mixture was mixed with itraconazole pre-sieved through a 600 μm sieve in a low-shear mixer at 96 rpm for 10 minutes. The ternary mixture was fed into a laboratory-scale vertical jet mill and placed under the conditions described in Table 7.

[0142] For stability assessment, 2 g of the powders obtained from Tests 1, 2, and 3 were stored in a sealed condition in an oven at 40 °C and 75 ± 5% relative humidity for 4 weeks, herein referred to as "stability assessment samples".

[0143] Table 7 - Summary of process parameters and formulation composition for Example 3.

[0144]

[0145] The particle size distribution of micronized materials was characterized by laser diffraction - summarized in Table 7. All tests showed particle sizes within the inhalable range.

[0146] Table 7 - Characterization of the micronized mixture product of Example 3.

[0147]

[0148] At 20 - 25 °C and a relative humidity of 50 ± 10%, the micronized products obtained in Tests 1, 2, and 3 and the stability assessment samples of the same tests were filled into HPMC Capsule No. 3 with a fill weight of 30 mg and driven using a Plastiape inhaler (flow rate 100 L / min, pressure drop 4 kPa).

[0149] The fine particle fraction (determined by FSI) of the filled capsules was 39.9 ± 0.1% of the ejected dose for API only, and 54.7 ± 1.4% and 52.0 ± 0.2% of the ejected dose for Tests 2 and 3 containing API, 20.0 wt% trehalose dihydrate / mannitol, and cholesterol - see Table 8. The fine particle fraction (determined by FSI) of the filled capsules obtained from the stability assessment samples was 53.5 ± 0.4% of the ejected dose for API only, and 52.4 ± 1.4% and 51.6 ± 1.0% of the ejected dose for Tests 2 and 3 containing API, 20.0 wt% trehalose dihydrate / mannitol, and cholesterol - see Table 8. This indicates that for high - dose itraconazole formulations, the pharmaceutical compositions containing sugars and cholesterol prepared by co - grinding can omit the powder conditioning step usually required after jet milling, because the formulations of the pharmaceutical compositions showed similar performance in terms of FPF after 4 weeks under accelerated stability conditions (only 4% and 1% change for Tests 2 and 3 respectively), while the ground formulation without excipients showed a 34% change and thus required a conditioning period until the final performance was reached.

[0150] Table 8 - Summary of capsule characterization of Example 3.

[0151]

[0152]

[0153] Example 4 - Co - grinding of Remdesivir with sugars and lipids

[0154] Tests 2, 3, and 4 were prepared by low - shear mixing and jet milling.

[0155] Test 1 (API only): Remdesivir was sieved through a 450 μm sieve and fed into a laboratory - scale vertical jet mill and placed under the conditions described in Table 8.

[0156] Experiment 2: Mannitol sieved through a 450 μm sieve and remdesivir sieved through a 450 μm sieve were mixed in a low-shear mixer at 96 rpm for 15 minutes. The previous mixture was fed into a laboratory-scale vertical jet mill and placed under the conditions described in Table 8.

[0157] Experiment 3: Cholesterol and remdesivir sieved through a 450 μm sieve were mixed in a low-shear mixer at 96 rpm for 15 minutes. The previous mixture was fed into a laboratory-scale vertical jet mill and placed under the conditions described in Table 8.

[0158] Experiment 4: Mannitol was sieved through a 450 μm sieve and mixed with cholesterol in a low-shear mixer at 96 rpm for 15 minutes. The previous mixture was mixed with remdesivir sieved through a 450 μm sieve in a low-shear mixer at 96 rpm for 15 minutes. The ternary mixture was fed into a laboratory-scale vertical jet mill and placed under the conditions described in Table 8.

[0159] Table 8 - Summary of process parameters and formulation composition of Example 4.

[0160]

[0161] The particle size distribution of the micronized materials was characterized by laser diffraction, and their crystalline state was characterized by XRPD - summarized in Table 9 and "Error! Reference source not found". All experiments showed particle sizes within the inhalable range, with Experiment 4 (cholesterol and mannitol) showing smaller particle sizes. These results indicate that the presence of these two excipients may contribute to particle breakage, and thus may result in a smaller PSD for similar micronization energy. The XRPD of the milled materials was the same as that of the API or the diffraction peaks of Experiments 2 and 3 with mannitol, indicating that the API and excipients are crystalline after micronization.

[0162] Table 9 - Characterization of micronized blends of Example 4.

[0163]

[0164] After micronization, the powders obtained in Experiments 1, 2, 3, and 4 were filled into HPMC size 3 capsules at 20 - 25 °C and 50 ± 10% relative humidity using an Auger filling Quantos device, with a target of 30 mg as labeled, a rejection limit of ±5%, and driven using a Plastiape inhaler (flow rate of 100 L / min, pressure drop of 4 kPa).

[0165] Table 10 summarizes the characterization of the aerodynamic performance of the prepared capsules by NGI.

[0166] In the presence of cholesterol, the filled capsules exhibited significantly different performance, quantified by the difference in FPF - "Error! Reference source not found": For Trials 1 and 2 (API only, and API and mannitol, respectively), the FPFs obtained were 37.0 ± 3.8% and 33.4 ± 1.8%, respectively, unaffected by the presence of mannitol. For Trials 3 and 4 (API and cholesterol, and API, mannitol, and cholesterol, respectively), the FPFs were 44.7 ± 1.4% and 44.0 ± 3.9%, respectively, thus approximately 20% higher than the previous trials. These results indicate that the presence of additives, particularly cholesterol, during the jet milling process described in the present invention leads to a significant improvement in performance.

[0167] Table 10 - Summary of capsule characterization for Example 4.

[0168]

[0169] Example 5 - Pharmaceutical formulation containing mannitol and cholesterol under a low - flow device.

[0170] The drug formulations described in Example 4 (co - milled remdesivir filled into capsules labeled 30 mg, Trials 1 to 4) were driven using a PowdAir inhaler (flow rate of 60 L / min, pressure drop of 4 kPa), and the results are shown in Table 11.

[0171] The emitted dose of the filled capsules was 3.6 ± 3.7 mg for API only, 4.9 ± 5.4 mg and 17.2 ± 14.4 mg for Trials 2 and 3 containing mannitol or cholesterol, respectively, and 26.0 ± 1.7 mg for Trial 4 containing cholesterol and mannitol. Thus, compared to the API - only formulation, the pharmaceutical composition prepared by co - milling containing a 10:1 ratio of sugar and cholesterol and an 89% concentration of API resulted in a 500% increase in ED, and for remdesivir, the relative standard deviation was reduced compared to formulations co - milled with mannitol or cholesterol only.

[0172] Table 11 - Summary of capsule characterization for Example 5.

[0173]

[0174] Dissolution data

[0175] As Figure 6As shown. This shows the dissolution curves of itraconazole formulations from Trial 1 (upper curve, with excipient) and Trial 3 (lower curve, API alone) of Example 1 at time points of 2, 15, 30, 60, and 90 minutes, performed in triplicate.

[0176] The dissolution medium was an aqueous solution of phosphate-buffered saline (PBS) at pH 7 maintained at 37 °C (Merck Millipore, Massachusetts, USA). The saturation concentration of itraconazole in this medium was 33 mg / L, so the sink conditions were ensured to be below 11 mg / L. Dissolution was carried out using a paddle-disk configuration in a Type II dissolutor apparatus (Copley Scientific, Nottingham, UK), rotating at 75 rpm for 2 hours at 3.5 cm above the disk, and the dissolution medium was 300 ml. Quantification was performed by ultraviolet (UV) spectrophotometry at a wavelength of 265 nm within 0.5 s using a 1.5 ml quartz cell and a 10 mm optical path in a Specord200Plus (Analytik Jena, Jena, Germany). Methanol was used as the solvent for other UV quantifications.

[0177] Methods and other definitions

[0178] NGI method

[0179] The NGI evaluation was performed using a pressure of 4 kPa, a volume of 4 L, and a single drive.

[0180] Conditioning step

[0181] In a typical conditioning step, the formulation was stored under controlled temperature and relative humidity conditions. The storage temperature was maintained above the glass transition temperature, and the relative humidity was set so that the dry powder could absorb moisture and then recrystallize (see, for example,

[19] Shetty et al., 2020).

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Claims

1. A pharmaceutical composition comprising composite particles having a controlled aerodynamic particle size distribution, wherein the composite particles comprise one or more crystalline forms of an active pharmaceutical ingredient (API), at least one sugar, and at least one lipid.

2. The pharmaceutical composition according to claim 1, wherein the particle size distribution of the composite particles is suitable for inhalation.

3. The pharmaceutical composition according to claim 1 or 2, wherein the particle size ranges from Dv90 < 20 μm.

4. The pharmaceutical composition according to claim 3, wherein the particle size ranges from Dv90 < 10 μm.

5. The pharmaceutical composition according to any one of the preceding claims, wherein the particle size ranges from 0.1 μm ≤ Dv90 ≤ 6 μm.

6. The pharmaceutical composition according to any one of the preceding claims, wherein the emitted dose obtained by a Dose Unit Sampling Apparatus (DUSA), a Fast Screening Impinger (FSI), or a Next Generation Impinger (NGI) is higher than the emitted dose of a pharmaceutical composition containing only the API when the two compositions are prepared under the same conditions.

7. The pharmaceutical composition according to any one of the preceding claims, wherein the fine particle fraction (FPF) obtained by DUSA, FSI, or NGI is higher than the fine particle fraction of a pharmaceutical composition containing only the API when the two compositions are prepared under the same conditions.

8. The pharmaceutical composition according to any one of the preceding claims, wherein the dissolution time of the pharmaceutical composition is reduced compared to a composition containing only micronized API.

9. The pharmaceutical composition according to any one of the preceding claims, wherein the physical stability and / or chemical stability of the pharmaceutical composition is increased compared to a composition containing only micronized API.

10. The pharmaceutical composition according to any one of the preceding claims, wherein the sugar is selected from mannitol, trehalose, trehalose hydrate, sucrose, lactose, or raffinose, or a combination of two or more thereof.

11. The pharmaceutical composition according to any one of the preceding claims, wherein the sugar is mannitol or trehalose, or a combination thereof.

12. The pharmaceutical composition according to any one of the preceding claims, wherein the lipid is selected from the group consisting of: saturated or unsaturated fatty acids; glycerides, including neutral glycerides or phosphoglycerides; non-glyceride lipids such as steroids, waxes, or sphingolipids; or a combination of two or more thereof.

13. The pharmaceutical composition according to any one of the preceding claims, wherein the lipid is selected from the group consisting of: steroids selected from the following steroid classes: cholestanes, cholanes, pregnanes, androstanes, or estranes; or phosphoglycerides selected from the group consisting of: phosphatidylcholine, phosphatidylglycerol, or phosphatidylethanolamine; or a combination of two or more thereof.

14. The pharmaceutical composition according to any one of the preceding claims, wherein the lipid is a steroid, such as cholesterol, or a phospholipid, and the phospholipid is selected from dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), dimyristoyl phosphatidylcholine (DMPC) or lecithin, or a combination of two or more thereof.

15. The pharmaceutical composition according to any one of the preceding claims, wherein the sugar comprises mannitol or trehalose, and the lipid comprises cholesterol.

16. The pharmaceutical composition according to any one of the preceding claims, wherein the weight % range of the components based on the total weight of the composition is as follows: API is 50 wt% to 99.5 wt%; sugar is 0.5 wt% to 45 wt%; and lipid is 0.01 wt% to 5 wt%.

17. The pharmaceutical composition according to claim 16, wherein the weight % range of the components based on the total weight of the composition is as follows: API is 80 wt% to 99.5 wt%; sugar is 0.5 wt% to 20 wt%; and lipid is 0.04 wt% to 2 wt%.

18. The pharmaceutical composition according to any one of the preceding claims, wherein the API is present in an amount of 30 wt% or more based on the weight of the total composition.

19. The pharmaceutical composition according to claim 18, wherein the API is present in an amount of 50 wt% or more based on the weight of the total composition.

20. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is a high-dose inhalation composition, and a single inhalation dose provides at least 2.5 mg of API or more.

21. The pharmaceutical composition according to any one of the preceding claims, which is used as a medicine.

22. The pharmaceutical composition according to claim 21, which is used for treating a patient's lung disease.

23. A dry powder inhaler, which comprises the pharmaceutical composition according to any one of the preceding claims.

24. The dry powder inhaler according to claim 23, which is a disposable inhaler.

25. The dry powder inhaler according to claim 23 or 24, wherein the dry powder inhaler comprises a mouthpiece, an inhaler body and a cartridge for receiving a dose.

26. The dry powder inhaler according to claim 24, 25 or 26, wherein the cartridge is movable relative to the inhaler body to provide a dose through the mouthpiece.

27. The dry powder inhaler according to claim 25 or 26, wherein the inhaler cartridge comprises one reservoir or a plurality of reservoirs.

28. The dry powder inhaler according to claim 27, wherein each reservoir provides a single dose.

29. A method for preparing the pharmaceutical composition according to any one of claims 1 to 20, the method comprising the following steps: a. mixing the API and one or more excipients into a homogeneous powder, the excipients comprising at least one sugar or at least one lipid, or both at least one sugar and at least one lipid; b. reducing the particle size distribution of the mixture.

30. The method according to claim 29, wherein step (b) is carried out without using a solvent.

31. The method according to claim 29 or 30, wherein step (b) comprises jet milling.

32. The method according to any one of claims 29 to 31, wherein the API and at least one sugar are first mixed and jet milled together, and then at least one lipid is mixed with the resulting pharmaceutical composition and jet milled to obtain a pharmaceutical composition comprising the API, at least one sugar and at least one lipid.

33. The method according to any one of claims 29 to 32, wherein the injection pressure in the jet milling step is 2 to 12 bar.

34. The method according to claim 33, wherein the injection pressure is 4 to 8 bar.

35. The method according to any one of claims 29 to 34, wherein the temperature in the particle size reduction step is 60 °C or lower.

36. The method according to claim 35, wherein the temperature in the particle size reduction step is 10 °C or lower.

37. The method according to any one of claims 29 to 35, wherein the temperature in the particle size reduction step is 20 °C or higher.

38. The method according to any one of claims 26 to 37, wherein no conditioning step is employed, or wherein a reduced amount of conditioning time is employed compared to the conditioning time required to condition a composition comprising only micronized API.

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