Crystalline pharmaceutical composition for inhalation containing sugar and lipid composite particles and production method

Abstract

The present invention describes a pharmaceutical composition comprising composite particles having a controlled aerodynamic particle size distribution, wherein the composite particles comprise one or more pharmaceutical active ingredients (APIs), at least one sugar, and at least one lipid. A method for manufacturing the pharmaceutical composition comprises: a. formulating the API and at least one sugar or at least one lipid, or both at least one sugar and at least one lipid, into a homogeneous powder; and b. reducing the particle size distribution of the formulation. The micronized pharmaceutical composition enables the delivery of crystalline and stable APIs with better aerodynamic properties than micronized API alone, and also improves downstream processing and stability characteristics.

Description

Detailed Description of the Invention

[0001] [Technical Field of the Invention] The present invention generally relates to the field of pharmaceutical dry powders, and more particularly to composite particles having enhanced aerodynamic performance for inhalation delivery.

[0002] One of the major advantages of pulmonary drug delivery is rapid clinical onset, which is due to the large surface area of the lung (>100 m2), in addition to perfusion by a large volume of blood (maximum flow rate 5.7 L / min) and a thin absorption membrane (0.1 - 0.2 μm) [1]. Furthermore, drug delivery to the lung enables avoidance of first-pass metabolism, increases bioavailability, reduces the required dose, and thus reduces the treatment cost. Transpulmonary drug administration has been used for many years for low-dose delivery for the purpose of treating conditions such as asthma. High-dose delivery by inhalation is of interest in that many new drugs exhibit low bioavailability when administered orally due to solubility or low absorption. In addition, for local delivery, lung delivery exhibits a reduction in systemic side effects and an increase in concentration at the site of action, and for systemic delivery, lung delivery improves the non-invasive administration of unstable molecules.

[0003] Pressurized metered-dose inhalers, nebulizers, and dry powder inhalers (DPIs) are common devices for drug delivery to the lung. Among these, dry powder inhalers are presumed to have the advantages of not containing propellants, not requiring coordination of actuation with inhalation, being easy to carry, relatively inexpensive, and providing high physical / chemical stability because the drug is kept in a solid state [2].

[0004] Inhaled powders are required to be within a specific particle size distribution (PSD) (50% (Dv50) of the particles by volume must be less than 5 μm) and have an aerodynamic mass median diameter (MMAD) of 1 - 5 μm so as to target the deep airways. A completely crystalline and moisture-free powder is preferred for improved stability.

[0005] The performance of DPI formulations is usually evaluated by the emitted dose (ED), which is the powder mass per capsule (mg / capsule) that detaches the capsule upon actuation, and the fine particle dose (FPD), which is the powder mass per capsule that flows through a 5-μm cut-off aerodynamic diameter upon actuation. The fine particle fraction (FPF) is another performance indicator and is obtained by dividing the FPD by either the ED or the labeled mass. The measured values of these performance indicators must all show a relative standard deviation (RSD) of less than 5%.

[0006] The flow properties of powders depend on the particle size distribution and are a major obstacle to the pulmonary route of administration; thus, particle size reduction is required to target the deep airways. The performance of fine powders is affected by particle size in that the relative importance of interparticle forces with respect to gravity increases as the particle size decreases: while gravity is proportional to the cube of the particle size, the van der Waals force is proportional to the particle size, so the van der Waals force becomes more relevant upon size reduction. Also, electrostatic, capillary, and mechanical interlocking are other relevant interparticle interactions and also depend on particle size and shape, and surface texture and contact area, surface energy, hygroscopicity, and relative humidity [2]. Particle shape can limit the approach of two particles, thereby reducing interparticle interactions. A similar effect can be caused by surface roughness: indeed, if the surface roughness is on the order of 1 μm, the van der Waals force is limited to negligible values [3]; the opposite is true when the particles are planar or elongated, allowing close contact. When the roughness size is large enough to cause capture of other particles, mechanical interlocking and uneven distribution of surface energy occur. Relative humidity plays a certain role in two opposing mechanisms, as it increases the interactions due to capillary forces (which can become stronger as the substance is more hygroscopic), but also increases conductivity, thereby dissipating the electrostatic charge. The charge is generated from collisions and friction between particles during powder mixing and other processing steps [2]. In general, the van der Waals force is dominant, and all these interactions are only relative for particles with diameters on the order of a few micrometers or less, and thus the particles become stickier and more prone to aggregation.

[0007] When delivering low doses, the most common strategy to ensure acceptable aerosolization and address the stickiness inherent in fine powders is to use coarser inert carriers such as lactose that separate upon inhalation, which remain in the device or deposit in the mouth or upper airway, allowing drug particles to redisperse in the airflow. For high-dose formulations (typically APIs delivered <5 mg), the use of a carrier is not suitable because saturation at the active sites of the carrier results in undesirable particle segregation. An alternative approach is to create soft aggregates of API without a carrier, which remain intact throughout the processing and readily deaggregate upon inhalation. However, due to the stickiness inherent in fine powders, stable aggregate formation can occur, which does not deaggregate during operation, thus not reaching the lower airway and significantly reducing the actually delivered dose, resulting in wide variability in carrier-free approaches [4].

[0008] Co-milling means co-processing two or more types of particles (e.g., API and lubricant) to produce composite particles with enhanced performance. The benefits obtained often result from 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, specifically by imparting increased wettability to the composite particles [5]. The excipients used in co-milling include a number of different types of compounds, which act by different mechanisms

[10] [9].

[0009] The improvement in the aerodynamic performance of co-milled formulations is explained by the excipient particles acting as spacers, reducing the contact area and preventing particle-particle interactions, and adhering to the high surface energy sites of the API particles [6]. In some cases, the excipient particles face the hydrophobic groups outwards and may form a coating film in some cases [7]. Generally, studies have explained the improvement of FPF by the reduction of surface energy [8][9]. Electrostatic stability has also been reported as a mechanism that provides long-term particle size stability through repulsion between particles and prevents particle aggregation

[10] .

[0010] Regarding the prevention of changes to the solid state and crystal defects that often occur during milling, co-milling has shown promising results

[11]

[12] . Mechanically induced amorphization competes with thermodynamically induced recrystallization, so that, in a general way, milling at a temperature below the glass transition temperature of the material results in conditions that preserve the amorphous state after the amorphous state has been induced by the shear hindrance effect, thus having a high potential to produce amorphous products. On the other hand, when co-milling techniques are used to lower the overall glass transition temperature of pharmaceutical compositions, the efficiency of recrystallization is about 10 times and no amorphization is observed. The amorphous state is inherently unstable, leading to recrystallization, which can promote the formation of solid bridges and the resulting agglomeration, so crystalline formulations are desirable. In addition, the amorphous state is more prone to water sorption and requires more stringent storage conditions. Furthermore, the control of the crystalline state of the API may lead to controlled release by avoiding supersaturation of the amorphous form in the internal fluid of the lung and is thus available for obtaining a therapeutic effect. This is one of the main benefits of the milling process compared to spray drying, which is known to produce amorphous products.

[0011] Stability is a crucial property of pharmaceutical powders. Particle size enlargement due to adhesion, water sorption due to amorphous regions, subsequent formation of solid bridges or drug degradation are all undesirable effects. Co-milling, as described above, is a potentially promising approach in improving the stability of pharmaceutical products in that it can be applied to minimize these effects. Also, some excipients are capable of forming a hydrophobic coating film that protects from moisture and degradation [7].

[0012] Smaller particles have a larger surface area and thus dissolve more rapidly, so particle size reduction alone is a promising approach for enhancing dissolution. The use of wetting agents in co-milling is an improved approach for this purpose as it allows the substance to spread more easily on the surface by incorporating a substance that reduces the surface tension of water. When these particles dissolve easily, the composite particles become porous API particles and it is possible to further increase the contact area.

[0013] U.S. Patent No. 8,802,149 relates to a pharmaceutical composition for inhalation containing active ingredients that are hydrophilic and hydrophobic compounds produced by spray drying. Spray-dried formulations containing hydrophilic and hydrophobic materials have been studied in the literature

[15]

[16] . However, this method is known to produce completely amorphous products, unlike, for example, jet mill grinding, and amorphous products are more prone to moisture sorption and stability problems, which can be extremely important in inhalation formulations where particle size / aggregate size determines the delivery dose. Also, compared to many grinding processes, spray drying involves the optimization of several steps (dissolution, atomization and recovery) as well as the use of solvents and is a more complex process.

[0014] U.S. Patent No. 8,182,838 describes a method that further includes the steps of jet milling active particles in the presence of particles of an amino acid, a metal salt of stearic acid, and / or a phospholipid to form composite active particles, and formulating carrier particles together with the composite active particles. However, as mentioned above, the carrier-based approach is not suitable for high dosing. Also, the safety of amino acids for pulmonary delivery has not been recognized, and the hydrophobicity of metal salts of stearic acid and phospholipids can also be harmful to dissolution, and they, especially the metal salts of stearic acid, can cause irritation by remaining in the airway for a long time. U.S. Patent No. 8,932,635 shows surface coating active particles for inhalation delivery with magnesium stearate for the purpose of retarding dissolution.

[0015] European Patent No. 1,663,155 describes a co-jet milling method for producing composite particles for pulmonary delivery, wherein the excipient contains an amino acid, a metal salt of stearic acid, or a phospholipid that coats the active particles. These materials have the aforementioned disadvantages.

[0016] U.S. Patent No. 11,103,448 describes a method of separately milling metal salt particles of stearic acid and active substance particles, and jet milling both the already milled active particles and the metal salt particles of stearic acid to obtain composite particles for inhalation. This method includes several steps and has disadvantages including the hydrophobicity of the metal salt of stearic acid and airway irritation described above.

[0017] Lo et al. generated carrier-based inhalable particles with enhanced performance by spray drying liposomes of API particles with sugars having a stabilizing function (sucrose, trehalose, and lactose) and lipids (DMPC, DPPC, DSPC, or DPPG)

[13] . As mentioned above, the carrier-based approach is not suitable for high dosing. Also, this method includes several steps.

[0018] U.S. Patent Application Publication No. 2007 / 178166 describes a method for preparing dry powder pharmaceutical formulations for transpulmonary or nasal administration. The API particles are blended with a first excipient to form a first powder blend, which is then milled. Subsequently, in a second step, the milled blend is blended with a second excipient to form a compounded dry powder. The particles of the second excipient are larger than the fine or nano particles of the milled blend.

[0019] International Publication No. 2022 / 126105 discloses methods, compositions, and kits for treating fibrotic lung diseases. This method utilizes a combination product for inhalation, including a dry powder formulation provided in an inhaler for administration by oral inhalation. The composition contains diketopiperazine particles, and the pharmaceutical dry powder is prepared by spray drying.

[0020] Chinese Patent No. 106102748 discloses a dry powder formulation containing acetylsalicylic acid particles and including milling and spray drying steps.

[0021] U.S. Patent Application Publication No. 2006 / 257491 describes mechanofusion and jet milling for the production of dry powders for pulmonary inhalation. The blend contains an API and additive substances such as amino acids / stearic acid metal salts / phosopholipids. The described formulations contain leucine (amino acid) or magnesium stearate (stearic acid metal), which may present safety issues or irritation regarding lung delivery due to the hydrophobicity of the compounds respectively.

[0022] Korean Patent Application Publication No. 2019 / 0068591 describes dry particles containing crystalline microparticles of an antifungal agent, focusing on the preparation of crystalline drugs treated with an antisolvent and a stabilizer to form a suspension. There is no disclosure regarding milling blends of different components to improve aerodynamic performance and / or stability.

[0023] [Description of the Invention] In a broad aspect, the present invention provides a pharmaceutical composition comprising one or more pharmaceutical active ingredients (APIs), at least one sugar, and at least one lipid. The composition has a controlled aerodynamic particle size distribution due to the manufacturing process. The API is in crystalline form. Preferably, the 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.

[0024] Preferably, the composition comprises composite particles. Such particles are composed of the active ingredient and at least two excipients in an individual particle. Preferred particles are composite particles comprising an API, a sugar component, and a lipid component. The composition is preferably prepared by co-milling.

[0025] In a further aspect, the present invention thus provides a pharmaceutical composition comprising composite particles comprising one or more pharmaceutical active ingredients (APIs) in crystalline form, at least one sugar, and at least one lipid. The particles have a controlled aerodynamic particle size distribution. Composite particles prepared by co-milling comprise one or more pharmaceutical active ingredients (APIs), at least one sugar, and at least one lipid and are thus an aspect of the present invention. Accordingly, co-milled composite particles comprising one or more pharmaceutical active ingredients (APIs), at least one sugar, and at least one lipid are provided. The present invention thus provides, in one aspect, crystalline composite particles.

[0026] Preferably, the particles of the composition are obtained using co-milling. Co-milling has been reported, for example, as co-processing of APIs / excipients with additive substances for composite particle production (see, for example, Lau et al., 2017

[18] ). The co-milled particles described are thus an aspect of the present invention. One aspect of the present invention is thus to co-mill an API, a sugar (such as mannitol), and a lipid (such as cholesterol) together to obtain composite particles. Such particles are preferably crystalline.

[0027] The present invention also provides a pharmaceutical composition disclosed and claimed herein for use as a medicament. For example, the pharmaceutical composition is for use in treating the lung condition of a patient.

[0028] As will be understood by those skilled in the art, the compositions of the present disclosure can be used, for example, in a dry powder inhaler. Any suitable dry powder inhaler can be used.

[0029] Accordingly, the present invention also provides a dry powder inhaler comprising the pharmaceutical composition disclosed and claimed herein.

[0030] In a further aspect, there is also provided a method for manufacturing the pharmaceutical composition disclosed and claimed herein, the method comprising: a. formulating one or more excipients comprising an API and at least one sugar or at least one lipid, or both at least one sugar and at least one lipid, into a homogeneous powder; and b. reducing the particle size distribution of the formulation. comprises.

[0031] In a preferred embodiment, step (b) is carried out without using a solvent.

[0032] Step (b) preferably includes co-milling of the particles. Step (b) also preferably includes jet milling, although other similar techniques can be used if desired. For example, co-milling by a wet milling method can also be used. As described below, in the context of the present invention, for example, high-pressure homogenization can be a useful technique.

[0033] 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. Also provided is a pharmaceutical composition comprising such composite particles. Preferably, the components of the composition are crystalline.

[0034] Thus, the present invention relates to a pharmaceutical composition for use in an inhalation preparation of composite particles produced by co - grinding, which contains at least one API together with at least one sugar and at least one lipid, and whose performance is improved by preventing inter - particle interaction and adhesion. The inventors have found that the enhanced performance obtained by using the pharmaceutical composition is reflected in improved stability, reduced amorphization, and improved dissolution, and in all cases, the amount of additive was minimal. Saccharides are widely used as carriers in DPIs and are known to improve wettability. However, surprisingly, the inventors have found that when added in very small amounts, saccharides can improve the FPF of the co - ground formulation. In addition, when compared with other hydrophilic compounds, saccharides improve patient compliance by adding taste and have the benefit of known biocompatibility resulting from their use as carriers over several decades, compared to other materials such as polymers or amino acids, whose toxicity to the lungs has not been studied as extensively. By including saccharides in inhalation preparations, adhesion is reduced by adhering to the API and acting as an inert spacer between drug microparticles. Lipids account for 90% of the surfactant present in the lungs and consist of 40% by weight of DPPC and smaller amounts of other lecithins and cholesterol, and these materials have obtained Generally Recognized as Safe (GRAS) status [7]. These compositions protect the drug from moisture and improve aerosolization due to their anti - adhesion properties. Cholesterol is a biocompatible material that reduces particle aggregation and provides the above - mentioned benefits through drug coating [7]

[14] . The melting points of these compounds are low, which hinders their application in techniques such as spray - drying. However, when used in a dry co - grinding process in combination with saccharides, these compounds have surprisingly proven to be suitable for reducing the fouling effect through this process while yielding particles with improved aerodynamic performance (fine particle fraction and emitted dose) and enhanced stability.

[0035] The pharmaceutical composition of the present invention, which is produced by co-grinding and contains crystalline composite particles of an API accompanied by saccharides and lipids, has enhanced performance and stability without preventing dissolution while preventing inter-particle interactions that cause aggregation by the use of a wetting agent (saccharide) and a biocompatible and biodegradable substance (lipid) that naturally exists in the lung. The particles for improving the aerodynamic performance described in this invention are different from those containing amino acids, metal stearates or phospholipids described in the prior art in that the improvement is not due to the anti-adhesion properties of the excipient, but due to the ability of sugar microparticles that adhere to the API active site and act as a spacer to prevent aggregation. The particles described in this invention also have the additional benefit of improving patient compliance through taste.

Brief Description of the Drawings

[0036]

Figure 1A

Figure 1B

Figure 1C

Figure 2A

Figure 2B

Figure 2C

Figure 2D

Figure 3A

Figure 3B

Figure 3C

Figure 3D

Figure 3E

Figure 4

Figure 5

Figure 6

[0037] The pharmaceutical composition of the present invention preferably contains a composite molecule having a particle size distribution suitable for inhalation. For example, the particle size distribution can be such that Dv90 is 20 μm or less. Dv90 is the point at which up to 90% of the total volume of the material in the sample is "contained" in the particle size distribution. In a preferred embodiment, the particle size distribution has a Dv90 of 10 μm or less.

[0038] In one aspect, the pharmaceutical composition according to the present invention can have a particle size distribution in the range of about 0.1 μm ≤ Dv90 ≤ 6 μm.

[0039] When the composition of the present invention is used, for example, in a typical dry powder inhaler, it generally has a higher emitted dose (ED) than other types of compositions, such as those that are otherwise similar or identical but contain only the API alone or the API and one excipient. Accordingly, the present invention also provides a pharmaceutical composition as described, wherein when the composition is prepared under the same conditions, the emitted dose obtained by measurement with, for example, a Dosage Unit Sampling Apparatus (DUSA), or a Fast screening impactor (FSI) or a Next Generation Impactor (NGI) is higher than that of a pharmaceutical composition containing only the API.

[0040] When the composition of the present invention is used, for example, in a typical dry powder inhaler, it has also been found to generally have a larger fine particle fraction (FPF) than other types of compositions, such as those that are otherwise similar or identical but contain only the API alone or the API and one excipient. Accordingly, the present invention also provides a pharmaceutical composition as described, wherein when the composition is prepared under the same conditions and measured by, for example, DUSA, or FSI or NGI, the obtained fine particle fraction (FPF) is higher than that of a pharmaceutical composition containing only the API.

[0041] The composition of the present invention has also been found to have excellent dissolution properties, typically better dissolution properties than those of other types of compositions, such as those that are otherwise similar or identical but contain only the API alone or the API and one excipient. Accordingly, the present invention also provides a pharmaceutical composition as described, wherein the dissolution time is reduced when compared to a composition containing the micronized API alone, all other aspects being the same.

[0042] The composition of the present invention also has good physical and / or chemical stability, which is typically better than that of other types of compositions, for example, compositions that are similar or identical in other respects but contain only the API alone or the API and only one excipient. Therefore, the present invention also provides a pharmaceutical composition as described, which has improved physical and / or chemical stability when compared with a composition containing only micronized API.

[0043] In the composition of the present invention, any pharmaceutically acceptable sugar can be used, but preferably a sugar suitable for use via the inhalation route in human patients is used. One sugar or a combination of two or more sugars can be used, but preferably a single sugar is used. Preferably, the sugar is selected from the group consisting of mannitol, trehalose, trehalose hemihydrate, sucrose, lactose or raffinose, or a combination of two or more thereof.

[0044] In one aspect, a pharmaceutical composition in which the composite particles contain a sugar that is mannitol or trehalose, or a combination thereof, is preferred. Mannitol is a particularly preferred type of sugar. The inventors have found that, for example, mannitol is advantageous over other sugars recognized for inhalation due to its low hygroscopicity and non-toxicity. Mannitol is also capable of providing a high dose of fine particles of the integrated drug upon aerosolization of the powder.

[0045] Any pharmaceutically acceptable lipid can be used in the composition of the present invention, but preferably a lipid suitable for use via the inhalation route in human patients is used. One lipid or a combination of two or more lipids can be used, but preferably a single lipid is used. Preferably, the lipid is selected from the group consisting of saturated or unsaturated fatty acids, glycerides including neutral glycerides or phosphoglycerides, steroids, waxes, or non-glyceride lipids such as sphingolipids, or a combination of two or more thereof.

[0046] In one aspect of the present invention, the lipid is a steroid selected from the following classes of steroids: cholestane, cholane, pregnane, androstane or estane; or a phosphoglyceride selected from the group including phosphatidylcholine, phosphatidylglycerol, or phosphatidylethanolamine; or a combination of two or more thereof.

[0047] In a preferred aspect, the lipid is selected from the class of steroids, particularly cholestane such as cholesterol. In a further preferred aspect, the lipid is selected from the group of phosphoglycerides or phospholipids, particularly dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC) or lecithin, or a combination of two or more thereof such as lipids. Cholesterol and DSPC are two particularly preferred lipids.

[0048] Cholesterol is, for example, the main neutral lipid component found in pulmonary surfactant, and the inventors have found that this results in good results when combined with sugar components such as those disclosed herein containing mannitol.

[0049] In one aspect, a pharmaceutical composition in which the composite particles contain mannitol or trehalose as sugar and cholesterol as lipid is preferred.

[0050] The pharmaceutical composition according to the present invention has a balance of raw materials in order to bring about a desired effect. Preferably, the individual components of the composition are present as follows, and the weight % of the components is expressed relative to the total weight of the composition.

[0051] The API component is preferably present in an amount of 50 to 99.5 wt%, and a preferred range is 80 to 99.5 wt% depending on the API. A range of 90 to 95 wt% can also be used.

[0052] The sugar component is preferably present in an amount of 0.5 to 45 wt%, and the preferred range is 0.5 to 20 wt% depending on the sugar. Preferred sugars such as mannitol can be used, for example, in the range of 5 to 20 wt%, particularly in the range of 10 wt% or more, for example, in the range of 10 to 20 wt%, for good effects.

[0053] The lipid component is preferably present in an amount of 0.01 to 5 wt%, and the preferred range is 0.04 to 2 wt% depending on the lipid. Preferred lipids such as cholesterol can be used, for example, in the range of 0.04 to 2 wt% for good effects.

[0054] Thus, in a broad aspect, a preferred pharmaceutical composition according to the present invention has the weight percentages of the components relative to the total weight of the composition in the following ranges: API 50 to 99.5 wt%, sugar 0.5 to 45 wt%, and lipid 0.01 to 5 wt%.

[0055] A further preferred pharmaceutical composition of the present invention has the weight percentages of the components relative to the total weight of the composition in the following ranges: API 80 to 99.5 wt%, sugar 0.5 to 20 wt%, and lipid 0.04 to 2 wt%.

[0056] Some preferred exemplary compositions are shown in Table 1 below.

Table 1

[0057] Some preferred ratios (by weight) of API:sugar:lipid are in the range of 89:10:1 to 90:5:5. Examples include 89:10:1, 94:5:1, and 90:5:5. One particularly preferred sugar of these ratios is mannitol, and particularly preferred lipids include cholesterol or DSPC.

[0058] In one aspect, the API is present at 30 wt% or more, or preferably at 50 wt% or more, based on the total weight of the composition.

[0059] The API per se can in principle be any API suitable for administration using a powder formulation, and in particular an API suitable for administration via the pulmonary route. The API can be, for example, an antifungal agent such as itraconazole, an antiparasitic drug such as ivermectin, or an antiviral drug such as remdesivir.

[0060] The present invention is useful in particular in that it enables the supply of a high dose of API via the inhalation route. Accordingly, the present invention provides the pharmaceutical composition described herein, where the composition is a high-dose inhalation composition that supplies a single inhalation dose of at least 2.5 mg or more, for example 5 mg or more, of the API. High dose can also refer to the case where the amount of API in the drug dose inhaled is more than 4% by weight of the dose (see, for example, Sibum et al., 2018; Adhikari et al., 2022

[20] ).

[0061] Regarding the inhaler, different types of inhalers can be used for the use of the composition of the present invention, but a dry powder inhaler is preferred and can be, for example, a single-use inhaler. As will be understood, preferably, the dry powder inhaler comprises a mouthpiece, an inhaler body and a cartridge for receiving the above dose. In a preferred embodiment, the cartridge can be moved relative to the inhaler body to enable administration via the mouthpiece. The dry powder inhaler used can include an inhaler in which the inhalation cartridge comprises one reservoir or a plurality of reservoirs. In a preferred embodiment, each reservoir of the cartridge of the inhaler supplies a single dose.

[0062] As described above, the method according to the present invention is, in a broad aspect, a. blending an API with one or more excipients comprising at least one sugar or at least one lipid, or both at least one sugar and at least one lipid, to form a homogeneous powder; b. reducing the particle size distribution of the blend and including.

[0063] Thus, in one aspect, step (a) may include formulating the API and the sugar, followed by step (b) for the formulation of the API and the sugar. In this case, the method includes further formulating the formulation of the API and the sugar, obtained after step (b), with the lipid component, and subjecting the resulting formulation to a second step (b) - that is, a further step (c) of reducing the particle size distribution of the formulation of the API and the sugar together with the lipid component. In a preferred aspect, step (c) is a co-milling step, for example co-milling by jet milling of the API plus sugar and lipid. Thus, the method of the present invention always includes at least one step, preferably a co-milling step, where at least one sugar and at least one lipid are together subjected to the step of reducing the particle size distribution of the formulation together with the API.

[0064] Thus, in a preferred aspect of the method of the present invention disclosed and claimed herein, the API and at least one sugar are first formulated and co-milled together, for example by jet milling, and then at least one lipid is formulated with the resulting pharmaceutical composition and jet milled to yield a pharmaceutical composition comprising the API, at least one sugar and at least one lipid.

[0065] Thus, the method of the present invention encompasses the possibility of two co-milling steps, if desired. A first co-milling step with only the sugar component (or only the lipid component) of the API, and a second co-milling step where the formulation of the API with the sugar component (or the formulation of the API with the lipid component) is properly co-milled with a second component that is not yet present, i.e., the lipid component or the sugar component.

[0066] Thus, a feature of the present invention is that both excipient components (i.e., sugar and lipid) are subjected to step (b), preferably by co-milling, together with the API. This is preferably by jet milling. This aids in achieving improved aerodynamic performance. Another preferred feature of the method is that no second formulation step is required after co-milling of the API, sugar and lipid.

[0067] Step (a) of the method can include formulating the API simultaneously with at least one sugar and at least one lipid, or can include formulating at least one sugar and at least one lipid sequentially. That is, the formulation of the sugar and lipid components can be carried out in order. The order of formulation is not important. Thus, for sequential formulation, either the sugar or the lipid can first be formulated with the API, followed by the second component.

[0068] The injection pressure in the jet milling step is, for example, preferably about 2 to about 12 bar. In one embodiment, the injection pressure ranges from about 4 to about 8 bar.

[0069] The temperature at which the size reduction step (step (b)) is carried out is preferably about 60 °C or lower.

[0070] In some embodiments, the temperature at which the size reduction step (step (b)) is carried out is about 10 °C or lower. This step can be, for example, a cryogenic jet milling step in which jet milling is carried out under cold conditions mainly to avoid the formation of an amorphous form.

[0071] In other embodiments, the temperature at which the size reduction step (step (b)) is carried out is about 20 °C or higher. Thus, a temperature of 20 °C to 60 °C is often suitable.

[0072] One advantage in the process of the present invention is that it is possible to omit the conditioning step. In a typical conditioning step, the formulations are stored under controlled temperature and relative humidity conditions during their manufacture. Thus, in a preferred embodiment, in the methods disclosed and claimed herein, the conditioning step is not used to produce a finally ready-to-use formulation, or a reduced amount of conditioning time is used compared to the conditioning time required to condition a composition containing the micronized API alone.

[0073] [Detailed Description of the Invention] In one embodiment, the present invention can be implemented by blending pre-screened (600 μm) API particles with, for example, pre-screened (600 μm) mannitol particles and cholesterol particles in a low-shear mixer, for example, at 96 rpm for 10 minutes. The resulting composition is then milled in a vertical jet mill using, for example, compressed nitrogen to generate a milling pressure of, for example, 6 bar and a venturi pressure of 7 bar, and the composition is fed into the jet mill apparatus at, for example, 40 g / hour. A jet mill is the simplest dry particle size reduction device, comprising a milling chamber (usually a flat disk shape with milling nozzles), where the raw material is fed through a venturi and compressed gas (usually air or nitrogen) is used to generate injection pressure and milling pressure through the nozzles, creating a vortex to promote particle-particle and particle-wall collisions, inducing fragmentation and subsequent size reduction. The resulting particle size distribution is manipulated by varying the milling pressure or the flow rate of the solid applied, and the venturi pressure is typically set to 1 bar or more to prevent backflow. For example, the resulting composition is filled into, for example, size 3 HPMC capsules, prepared for operation using a DPI device, in an amount of 20 - 50 mg.

[0074] According to the target airway region, different aerodynamic particle sizes can be produced. By changing the specific energy used in the grinding process, it becomes possible to obtain different particle sizes. Performing co-jet mill grinding at a grinding pressure in the range of 2 to 6 bar leads to a reduction in the particle size distribution to an inhalable size for some APIs, but a pressure of 6 to 12 bar is required for harder APIs. The temperature at which the process is carried out affects the mobility of the particles, thereby affecting the brittle and ductile regions of the material. For some materials, co-grinding in the temperature range of 0 to 20 °C may be required to obtain sufficient brittleness. For other materials, co-grinding at a temperature of 20 to 60 °C is required due to the adhesion of additive particles to the active particles. Wet methods such as high-pressure homogenization can also be used to carry out co-grinding if desired. This method can supply round particles, for example, in addition to producing a narrower particle size distribution, contrary to a jet mill where the particle shape is not controlled. Co-grinding with a specific excipient at a weight percentage of 0.5% has been reported to significantly improve the aerodynamic performance [9]. On the other hand, an additive amount of up to 20% is beneficial when handling certain active particles.

[0075] The formulations in the examples of the present invention 1) Turbula (Willy A. Bachofen AG, Basel, Switzerland) low-shear mixing device 2) Laboratory-scale jet mill MCOne (Jetpharma Solutions SA, Balerna, Switzerland) were processed using.

[0076] All materials except cholesterol were hand-sieved to the sizes specified in each example. The compounding and grinding conditions were also specified in each example, and these conditions are based on the applicant's previous grinding experience.

[0077] The formulations in the examples of the present invention included one or more of the following materials: Lactose Respitose SV003, manufactured by DFE Pharma, Germany Mannitol Pearlitol, manufactured by Roquet, USA Trehalose dihydrate, manufactured by Sigma Aldrich, USA Cholesterol, manufactured by Sigma Aldrich, USA Itraconazole, manufactured by Fagron Iberica, Spain Ivermectin, manufactured by Hovione PharmaScience, Portugal Remdesivir, manufactured by Hangzhou MolCore BioPharmatech Co., Ltd

[0078] The formulations in the examples of the present invention were characterized by the following techniques: A Helos laser diffraction machine was combined with a Rodos dry dispersion unit and an Aspiros module (Sympatec GmbH, Germany) and used to measure the particle size distribution of most formulations. Dispersion pressures of 0.1 bar (using an R2 lens (0.45 - 87.5 μm), focal length 50 mm) and 5 bar (using an R1 lens (0.18 - 35 μm), focal length 20 mm) were applied for the purpose of determining the size of either aggregates or single particles, respectively. The speed was maintained at 50 mm / second. All measurements were repeated twice.

[0079] Hydroxypropyl methylcellulose (HPMC) size 3 capsules (Capsugel, Colmar, France) containing 30 mg ± 1.5 mg of powder were used for all in vitro aerosolization studies. All were tested on a Fast-Screening Impactor (FSI) (Copley Scientific, Nottingham, UK) with 15 ml of dissolution medium in a pre-separator connected to a vacuum pump (Copley Scientific, Nottingham, UK) at either a flow rate of 60 L / min or 100 L / min for two actuations of the same capsule. Quantification of the emitted dose (ED) was performed gravimetrically by weighing the inhalation device and the capsule before and after actuation, and the fine particle dose (FPD) was measured gravimetrically by weighing the filter before and after actuation. The cut-off size of the pre-separator was 5 μm, and thus the fraction of the indicated mass reaching the filter (fine particle dose) was the fine particle fraction (FPF). The ED included all of the API that passed through the inhalation device. Some formulations were characterized on a Next Generation Impactor (NGI) (Copley Scientific, Nottingham, UK) using a vacuum pump (Copley Scientific, Nottingham, UK) connected to the pre-separator. The cups of the NGI were coated with 1 mL of an ethanol solution (v / v) of 1% glycerol. 15 ml of dissolution medium was placed in the pre-separator. Each test consisted of one actuation of the capsule for 4 seconds or 2.4 seconds respectively into the NGI using a DPI device at either 60 L / min or 100 L / min. The tests were repeated 3 times. 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, but the mass balance of the recovered material was ensured to be less than 15% error. All aerodynamic performance experiments were repeated 3 times.

[0080] The X-ray powder diffraction (XRPD) pattern was obtained by a PANalytical (Malvern, UK) X’Pert PRO X-ray diffraction system using Cu K irradiation (λ = 1.54 Å). The voltage and current intensity of the generator were set to 45 kV and 40 mA, respectively. The 2θ scanning range was 4° to 40°, the step size was 0.0131303°, and the count time was 99.450 seconds per step. The sample was filled using the zero background technique. Example 1 - Co-grinding of Itraconazole with Sugar and Lipid Test subjects 1, 2, 3, 4, and 5 were prepared by low-shear mixing and jet milling.

[0081] Test subject 1: Mannitol and cholesterol, pre-screened using a 600 μm sieve, were blended in a low-shear mixer at 96 rpm for 10 minutes. The pre-formulation was then blended with itraconazole, pre-screened using a 600 μm sieve, in a low-shear mixer at 96 rpm for 10 minutes. The blend of these three components was fed into a laboratory-scale vertical jet mill and subjected to the conditions described in Table 1.2.

[0082] Test subject 2: Mannitol, pre-screened using a 600 μm sieve, was blended with itraconazole, pre-screened using a 600 μm sieve, in a low-shear mixer at 96 rpm for 10 minutes. The blend was fed into a laboratory-scale vertical jet mill and subjected to the conditions described in Table 1.2.

[0083] Test subject 3: (API alone): Itraconazole was screened using a 600 μm sieve, fed into a laboratory-scale vertical jet mill, and subjected to the conditions described in Table 1.2.

[0084] Test Subject 4: Trehalose dihydrate and cholesterol that had been pre-screened using a 600-μm sieve were blended for 10 minutes at 96 rpm using a low-shear mixer. The pre-formulation was itraconazole that had been pre-screened using a 600-μm sieve and blended for 10 minutes at 96 rpm using a low-shear mixer. The formulation consisting of these three components was fed into a laboratory-scale vertical jet mill and subjected to the conditions described in Table 1.2.

[0085] Test Subject 5: Mannitol and cholesterol that had been pre-screened using a 600-μm sieve were blended for 10 minutes at 96 rpm using a low-shear mixer. The pre-formulation was itraconazole that had been pre-screened using a 600-μm sieve and blended for 10 minutes at 96 rpm using a low-shear mixer. The formulation consisting of these three components was fed into a laboratory-scale vertical jet mill and subjected to the conditions described in Table 1.2.

Table 2

[0086] The micronized materials were characterized for particle size distribution by laser diffraction, for crystalline state by XRPD, and for morphology by SEM, and summarized in Table 2, Error! Reference source not found. and Error! Reference source not found.

[0087] All test subjects exhibited particle sizes within the inhalable range. Error! Reference source not found. (particle size distribution of Test Subject 3) and Error! Reference source not found. (particle size distribution of Test Subject 5) showed only one (similar) particle population, indicating either that composite particles were formed or that the API and excipients were micronized to a similar extent.

[0088] The milled materials exhibited the same XRPD as the diffraction peaks of the API alone (Test Subject 3) or with mannitol (Test Subjects 1, 2, and 5) or trehalose dihydrate (Test Subject 4), indicating no change in the solid state of the materials.

[0089] SEM micrographs of Test Object 3 which is API alone and Test Object 5 which is the material co-milled with mannitol and cholesterol show that the presence of the excipient has no obvious effect on the particle morphology.

Table 3

[0090] Following micronization, the powders obtained from each test object were filled into size 3 HPMC capsules with a filling weight of 30 mg at 20 - 25°C and 50 ± 10% RH. Each capsule was operated using a Plastiape inhaler (flow rate of 100 L / min at a pressure drop of 4 kPa).

[0091] The manufactured capsules were characterized for their aerodynamic performance by FSI and summarized in Table 3.

[0092] The results of Test Objects 1, 2, and 3 show an improvement in the fine particle fraction from the release amount of 39.9 ± 0.1% for API alone (Test Object 3) to 50 ± 1.2% for Test Object 2 containing API and mannitol, and to 59.4 ± 0.9% for Test Object 1 containing API, mannitol, and cholesterol. These results demonstrate that the pharmaceutical composition containing sugar and cholesterol produced by co-milling significantly improves the aerodynamic performance compared to co-milling with sugar alone. The results of Test Objects 3, 4, and 5 show an improvement in the fine particle fraction (FPF) from the release amount of 39.9 ± 0.1% for API alone (Test Object 3) to 55.7 ± 0.5% for Test Object 4 containing API, trehalose dihydrate, and cholesterol, and to 56.5 ± 1.1% for Test Object 5 containing API, mannitol, and cholesterol.

[0093] These results show that the improvement obtained with the pharmaceutical composition containing sugar and cholesterol produced by co-milling improves the aerodynamic performance through excipients in different weight percentage ranges (Test Object 4 has 0.5 wt% excipient, Test Object 1 has 5 wt% excipient, and Test Object 5 has 10.3 wt% excipient).

Table 4

[0094] Example 2 - Co - grinding of Ivermectin with Sugar and Lipid Test subjects 2 and 3 were prepared by low - shear mixing and jet - mill grinding.

[0095] Test subject 1 (API alone): Ivermectin was sieved using a 600 - μm sieve, charged into a laboratory - scale vertical jet mill, and subjected to the conditions described in Table 4.

[0096] Test subject 2: Mannitol and cholesterol, which had been previously sieved using a 600 - μm sieve, were blended at 96 rpm for 10 minutes in a low - shear mixer. The previous blend was prepared by blending ivermectin, which had been previously sieved using a 600 - μm sieve, with the low - shear mixer at 96 rpm for 10 minutes. The blend consisting of these three components was charged into a laboratory - scale vertical jet mill and subjected to the conditions described in Table 4. Test subject 3: Mannitol and cholesterol, which had been previously sieved using a 600 - μm sieve, were blended at 96 rpm for 10 minutes in a low - shear mixer. The previous blend was prepared by blending ivermectin, which had been previously sieved using a 600 - μm sieve, with the low - shear mixer at 96 rpm for 10 minutes. The blend consisting of these three components was charged into a laboratory - scale vertical jet mill and subjected to the conditions described in Table 4.

Table 5

[0097] The micronized materials were summarized in Table 5 and Error! Reference source not found. for particle size distribution by laser diffraction and for crystalline state by XRPD. All the test subjects showed particle sizes within the inhalable range, but the particle sizes exhibited by Test Subject 3 (with a lower API content and higher mannitol and cholesterol contents) were relatively small. These results indicate that the presence of the two excipients facilitates particle breakage and thus results in a smaller PSD for a similar specific micronization energy. The milled materials exhibited the same XRPD as the diffraction peaks containing API or mannitol for Test Subjects 2 and 3, indicating that the API and excipients are crystalline after micronization.

Table 6

[0098] Following micronization, the powders obtained from Test Subjects 1, 2, and 3 were manually filled into size 3 HPMC capsules at 20 - 25 °C and 50 ± 10% RH with a target fill weight of 30 mg and operated using a Plastiape inhaler (flow rate of 100 L / min at a pressure drop of 4 kPa) to evaluate the aerodynamic performance.

[0099] The filled capsules had a fine particle fraction (determined by weight measurement FSI) of 14.1 ± 2.1% release for API alone and 31.6 ± 0.5% and 41.9 ± 1.4% release for Test Subjects 2 and 3 containing API, mannitol, and cholesterol at weight percentages of 9.4 and 20.0% respectively - see Table 6. The results showed that the pharmaceutical compositions containing sugar and cholesterol and produced by co - milling had a beneficial effect on both the release amount and the amount of fine particles with respect to the aerodynamic performance of a high - dose ivermectin formulation. The effect increased continuously with the addition of excipients, and the FPA reached almost three times that of the formulation milled without excipients.

Table 7

[0100] Example 3 - Conditioning of co - milled itraconazole high - dosage formulations Test subjects 2 and 3 were prepared by low - shear mixing and jet - mill grinding.

[0101] Test subject 1 (API alone): Itraconazole was sieved using a 600 - μm sieve, charged into a laboratory - scale vertical jet mill, and subjected to the conditions described in Table 7.

[0102] Test subject 2: Trehalose dihydrate and cholesterol, pre - sieved using a 600 - μm sieve, were blended in a low - shear mixer at 96 rpm for 10 minutes. The pre - blend was then blended with itraconazole, pre - sieved using a 600 - μm sieve, in a low - shear mixer at 96 rpm for 10 minutes. The blend consisting of these three components was charged into a laboratory - scale vertical jet mill and subjected to the conditions described in Table 7.

[0103] Test subject 3: Mannitol and cholesterol, pre - sieved using a 600 - μm sieve, were blended in a low - shear mixer at 96 rpm for 10 minutes. The pre - blend was then blended with itraconazole, pre - sieved using a 600 - μm sieve, in a low - shear mixer at 96 rpm for 10 minutes. The blend consisting of these three components was charged into a laboratory - scale vertical jet mill and subjected to the conditions described in Table 7.

[0104] For stability evaluation, 2 g of the powders obtained from test subjects 1, 2, and 3 were stored in a sealed state in an oven at 40 °C and 75 ± 5% RH for 4 weeks, which is referred to as the "stability evaluation sample" in this specification. [Table 8]

[0105] The micronized materials were characterized for particle - size distribution by laser diffraction and summarized in Table 7. All test subjects exhibited particle sizes within the inhalable range.

[0106] [Table 9] The micronized products obtained from Test Subjects 1, 2, and 3 and the stabilization evaluation samples of the same test subjects were filled into size 3 HPMC capsules at 20 - 25 °C and 50 ± 10% RH with a filling weight of 30 mg and operated using a Plastiape inhaler (flow rate of 100 L / min at a pressure loss of 4 kPa).

[0107] The filled capsules had a fine particle fraction (determined by FSI) of 39.9 ± 0.1% release for API alone, 54.7 ± 1.4 and 52.0 ± 0.2% release for Test Subjects 2 and 3 containing API, trehalose dihydrate / mannitol, and cholesterol at 20.0% by weight percentage each - see Table 8. The filled capsules obtained from the stability evaluation samples had a fine particle fraction (determined by weight - measured FSI) of 53.5 ± 0.4% release for API alone, 52.4 ± 1.4 and 51.6 ± 1.0% release for Test Subjects 2 and 3 containing API, trehalose dihydrate / mannitol, and cholesterol at 20.0% by weight percentage each - see Table 8. This indicates that the pharmaceutical compositions containing sugar and cholesterol and produced by co - grinding can generally omit the powder conditioning step required after jet milling for high - dose itraconazole formulations, as the formulations of said pharmaceutical compositions showed similar performance regarding FPF after 4 weeks under accelerated stability conditions (only 4% and 1% change for Test Subjects 2 and 3 respectively), while the formulations milled without excipients showed a 34% change and thus required a conditioning period until the final performance was achieved.

Table 10

[0108] Example 4 - Co - grinding of Remdesivir with Sugar and Lipid Test Subjects 2, 3, and 4 were prepared by low - shear mixing and jet milling.

[0109] Test Subject 1 (API alone): Remdesivir was sieved using a 450 μm sieve, charged into a laboratory-scale vertical jet mill, and subjected to the conditions described in Table 8.

[0110] Test Subject 2: Mannitol, pre-sieved using a 450 μm sieve, was blended with remdesivir, pre-sieved using a 450 μm sieve, in a low-shear mixer at 96 rpm for 15 minutes. This pre-blend was charged into a laboratory-scale vertical jet mill and subjected to the conditions described in Table 8.

[0111] Test Subject 3: Cholesterol was blended with remdesivir, pre-sieved using a 450 μm sieve, in a low-shear mixer at 96 rpm for 15 minutes. This pre-blend was charged into a laboratory-scale vertical jet mill and subjected to the conditions described in Table 8.

[0112] Test Subject 4: Mannitol and cholesterol, pre-sieved using a 450 μm sieve, were blended in a low-shear mixer at 96 rpm for 15 minutes. The pre-blend was then blended with remdesivir, pre-sieved using a 450 μm sieve, in a low-shear mixer at 96 rpm for 15 minutes. The blend consisting of these three components was charged into a laboratory-scale vertical jet mill and subjected to the conditions described in Table 8. [Table 11]

[0113] The micronized materials were summarized for particle size distribution by laser diffraction and for crystalline state by XRPD in Table 9 and Error! Reference source not found. All test subjects exhibited particle sizes within the inhalable range, although Test Subject 4 (cholesterol and mannitol) exhibited relatively small particle sizes. These results indicate that the presence of the two excipients facilitates particle breakage and thus results in a smaller PSD for a similar specific micronization energy. The milled materials exhibited the same XRPD as the diffraction peaks containing the API or mannitol in Test Subjects 2 and 3, indicating that the API and excipients are crystalline after micronization.

Table 12

[0114] Following micronization, the powders obtained from Test Subjects 1, 2, 3, and 4 were filled into size 3 HPMC capsules using an auger filling Quantos equipment targeting 20 - 25°C and 50 ± 10% RH, a labeled amount of 30 mg, and a discard limit of ±5%, and operated using a Plastiape inhaler (flow rate of 100 L / min at a pressure drop of 4 kPa).

[0115] The manufactured capsules were characterized for aerodynamic performance by NGI and summarized in Table 10.

[0116] When the filled capsules were quantified by the difference in FPF, they exhibited significantly different performance in the presence of cholesterol - Error! Reference source not found.: For Test Subjects 1 and 2 (API alone and API and mannitol, respectively), the FPF obtained was 37.0 ± 3.8% and 33.4 ± 1.8%, respectively, and there was no effect of the presence of mannitol. For Test Subjects 3 and 4 (API and cholesterol, and API, mannitol, and cholesterol, respectively), the FPF was 44.7 ± 1.4% and 44.0 ± 3.9%, respectively, and thus approximately 20% higher than the previous test subjects. These results indicate that the presence of additives, particularly cholesterol, in the jet - mill grinding process described in the present invention leads to a significant improvement in performance.

Table 13

[0117] Example 5 - Pharmaceutical Formulation Containing Mannitol and Cholesterol and Low - Flow Devices The pharmaceutical formulations described in Example 4 (co - milled remdesivir filled into capsules with a labeled amount of 30 mg, Test Subjects 1 - 4) were operated using a PowdAir inhaler (flow rate of 60 L / min at a pressure drop of 4 kPa), and the results are presented in Table 11.

[0118] The filled capsules have a release amount of 3.6 ± 3.7 mg for API alone, 4.9 ± 5.4 mg and 17.2 ± 14.4 mg for Test Subjects 2 and 3 containing mannitol or cholesterol, respectively, and 26.0 ± 1.7 mg for Test Subject 4 containing cholesterol and mannitol. Therefore, the pharmaceutical composition produced by co-grinding, containing sugar and cholesterol in a ratio of 10:1 and having an API concentration of 89%, shows a 500% improvement in ED for remdesivir compared to the API-alone formulation, and a reduction in relative standard deviation compared to the formulation co-ground with mannitol or cholesterol alone.

Table 14

[0119] Dissolution data This is shown in Figure 6. This shows the dissolution profiles of the itraconazole formulations from Example 1 performed 3 times at 2, 15, 30, 60, and 90 minutes for Test Subject 1 (upper trace, containing excipient) and Test Subject 3 (lower trace, API only).

[0120] The dissolution medium was phosphate-buffered saline (PBS) at pH 7 (Merck Millipore, Massachusetts, USA) and maintained at 37°C. Since the saturation concentration of itraconazole in this medium was 33 mg / L, sink conditions were ensured to be less than 11 mg / L. Dissolution was carried out for 2 hours using 300 ml of the dissolution medium in a paddle-over-disk configuration with a disk rotating at 75 rpm 3.5 cm above it in a type II dissolution apparatus (Copley Scientific, Nottingham, UK). Quantification was performed by ultraviolet (UV) spectrophotometry with a Specord 200 Plus (Analytik Jena, Jena, Germany) using a 1.5 ml quartz cell with a 10 mm optical path length and performed at a wavelength of 265 nm for 0.5 seconds. Other quantifications by UV were carried out using methanol as the solvent. Method and further definitions NGI method The NGI assessment was carried out using a pressure of 4 kPa, a volume of 4 L, and one actuation. Conditioning step

[0121] In a typical conditioning step, the formulation is stored under controlled temperature and relative humidity conditions. The storage temperature is maintained above the glass transition temperature, and the relative humidity is set such that moisture absorption by the dry powder and subsequent recrystallization are possible (see, for example, Shetty et al., 2020

[19] ).

[0122] References

[13] Liposomes and disaccharides as carriers in spray-dried powder formulations of superoxide dismutase, Lo Y; Tsai J, Kuo J [2] X. M. Zeng, G. P. Martin, and C. Marriott. Particulate Interactions in Dry Powder Formulation for Inhalation. CRC Press, oct 2000. doi: 10.3109 / 9780203209592. [1] J. Hu, Y. Dong, G. Pastorin, W. K. Ng, and R. B. Tan. Spherical agglomerates of pure drug nanoparticles for improved pulmonary delivery in dry powder inhalers. Journal of Nanoparticle Research, 15(4), 2013. ISSN 1572896X. doi: 10.1007 / s11051-013-1560-2. [4] M. L. H. Ong. The aerosol performance and physico - chemical properties of co - milled dry powder formulations for high dose delivery. PhD thesis, 2016. URL https: / / ses.library.usyd.edu.au / handle / 2123 / 16277. [3] J. Visser. Van der Waals and other cohesive forces affecting powder fluidization. Powder Technology, 58(1):1 - 10, 1989. ISSN 00325910. doi: 10.1016 / 0032 - 5910(89)80001 - 4. [5] Z. Huang, L. Lin, C. Mc Goverin, H. Liu, L. Wang, Q. T. Zhou, M. Lu, and C. Wu. Dry powder inhaler formulations of poorly water - soluble itraconazole: A balance between in - vitro dissolution and in - vivo distribution is necessary. International Journal of Pharmaceutics, 551(1 - 2):103 - 110, 2018. ISSN 18733476. doi: 10.1016 / j.ijpharm.2018.09.018. URL https: / / doi.org / 10.1016 / j. ijpharm.2018.09.018. [7] G. Pilcer and K. Amighi. Formulation strategy and use of excipients in pulmonary drug delivery. International Journal of Pharmaceutics, 392(1-2):1-19, 2010. ISSN 03785173. doi: 10.1016 / j.ijpharm.2010.03.017. URL http: / / dx.doi.org / 10.1016 / j.ijpharm.2010.03.017. [9] S. Mangal, H. Park, R. Nour, N. Shetty, A. Cavallaro, D. Zemlyanov, K. Thalberg, V. Puri, M. Nicholas, A. S. Narang, and Q. T. Zhou. Correlations between surface composition and aerosolization of jet-milled dry powder inhaler formulations with pharmaceutical lubricants. International Journal of Pharmaceutics, 568, sep 2019. ISSN 18733476. doi: 10.1016 / j.ijpharm.2019. 118504. URL https: / / pubmed.ncbi.nlm.nih.gov / 31299339 / . [8] K. Stank and H. Steckel. Physico-chemical characterisation of surface modified particles for inhalation. International Journal of Pharmaceutics, 448(1):9-18, 2013. ISSN 03785173. doi: 10.1016 / j.ijpharm.2013.03.009. URL http: / / dx.doi.org / 10.1016 / j.ijpharm.2013.03.009.

[10] M. George and I. Ghosh. Identifying the correlation between drug / stabilizer properties and critical quality attributes (CQAs) of nanosuspension formulation prepared by wet media milling technology. European Journal of Pharmaceutical Sciences, 48(1-2):142-152, 2013. ISSN 09280987. doi: 10.1016 / j.ejps.2012.10.004. URL http: / / dx.doi.org / 10.1016 / j.ejps.2012.10.004.

[11] Y. Amharar, V. Curtin, K. H. Gallagher, E. O’Siochru, P. O’Connell, and A. M. Healy. Mitigating unwanted amorphisation: A screening method for the selection of suitable excipients. European Journal of Pharmaceutical Sciences, 81:181-188, 2016. ISSN 18790720. doi: 10.1016 / j.ejps.2015. 10.016. URL http: / / dx.doi.org / 10.1016 / j.ejps.2015.10.016. [6] S. Aziz, R. Scherlie, and H. Steckel. Development of high dose oseltamivir phosphate dry powder for inhalation therapy in viral pneumonia. Pharmaceutics, 12(12):1-21, 2020. ISSN 19994923. doi: 10.3390 / pharmaceutics12121154.

[12] V. Curtin, Y. Amharar, Y. Hu, A. Erxleben, P. McArdle, V. Caron, L. Tajber, O. I. Corrigan, and A. M. Healy. Investigation of the capacity of low glass transition temperature excipients to minimize amorphization of sulfadimidine on co-milling. Molecular Pharmaceutics, 10(1):386 - 396, jan 2013. ISSN 15438384. doi: 10.1021 / mp300529a. URL https: / / pubs.acs.org / doi / abs / 10.1021 / mp300529a.

[14] X. Hu, C. Wang, L. Wang, Z. Liu, L. Wu, G. Zhang, L. Yu, X. Ren, P. York, L. Sun, J. Zhang, and H. Li. Nanoporous CD - MOF particles with uniform and inhalable size for pulmonary delivery of budesonide. International Journal of Pharmaceutics, 564(November 2018):153 - 161, 2019. ISSN 18733476. doi: 10.1016 / j.ijpharm.2019.04.030.

[15] M. Malamatari, A. Charisi, S. Malamataris, K. Kachrimanis, I. Nikolakakis. Spray Drying for the Preparation of Nanoparticle - Based Drug Formulations as Dry Powders for Inhalation. MDPI Processes, 788 (2020): ISSN 2227 - 9717. doi: 10.3390 / pr8070788

[16] J. Dolatabadi, H. Hamishehkar, H.Valizadeh. Development of dry powder inhaler formulation loaded withalendronate solid lipid nanoparticles: solid-state characterization and aerosoldispersion performance. Drug Development and Industrial Pharmacy, 41 (September2014): 1431-1437. doi: 10.3109 / 03639045.2014.956111

[17] Adhikari et al, Solid state ofinhalable high dose powders, Advanced Drug Delivery Reviews. 2022, 189:114468.doi:10.1016 / j.addr.2022.114468.

[18] Lau et al, A review of co-millingtechniques for the production of high dose dry powder inhaler formulation, DrugDevelopment and Industrial Pharmacy. 2017. doi:10.1080 / 03639045.2017.1313858.

[19] Shetty et al, Physical stability ofdry powder inhaler formulations, Expert Opin Drug Deliv. 2020, 17(1): 77-96.doi:10.1080 / 17425247.2020.1702643.

[20] Sibum et al, Challenges for pulmonary delivery of high powder doses, International Journal of Pharmaceutics. 2018, 548:325-336. Doi:10.1016 / j.ijpharm.2018.07.008.

Claims

1. A pharmaceutical composition comprising composite particles having a controlled aerodynamic particle size distribution, wherein the composite particles comprise one or more active pharmaceutical ingredients (APIs) in crystalline form, at least one sugar, and at least one lipid. The above composition is prepared by co-grinding, and the lipids include cholesterol. The composition is a pharmaceutical composition comprising the sugar in an amount of 0.5 to 45 wt% based on the total weight of the composition.

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 range is Dv90 < 20 μm.

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

5. The pharmaceutical composition according to claim 1 or 2, wherein the particle size range is 0.1 μm ≤ Dv90 ≤ 6 μm.

6. The pharmaceutical composition according to claim 1 or 2, wherein, when the composition is prepared under the same conditions, the amount released by a dose-unit sampling device (DUSA), a high-speed screen impactor (FSI), or a next-generation impactor (NGI) is higher than that of a pharmaceutical composition containing API alone.

7. The pharmaceutical composition according to claim 1 or 2, wherein, when the composition is prepared under the same conditions, the particulate fraction (FPF) obtained by DUSA, FSI, or NGI is higher than that of the pharmaceutical composition containing API alone.

8. The pharmaceutical composition according to claim 1 or 2, wherein the dissolution time is reduced compared to a composition containing the micronized API alone.

9. The pharmaceutical composition according to claim 1 or 2, wherein the physical and / or chemical stability is improved when compared to a composition containing the micronized API alone.

10. The pharmaceutical composition according to claim 1 or 2, wherein the sugar is selected from the group comprising mannitol, trehalose, trehalose high-crate, sucrose, lactose, or raffinose, or a combination of two or more thereof.

11. The pharmaceutical composition according to claim 1 or 2, wherein the sugar is mannitol or trehalose, or a combination thereof.

12. The pharmaceutical composition according to claim 1 or 2, wherein the lipid further comprises a lipid selected from the group including saturated or unsaturated fatty acids, glycerides containing neutral glycerides or phosphoglycerides, steroids, waxes, or non-glycerid lipids such as sphingolipids, or combinations of two or more thereof.

13. The pharmaceutical composition according to claim 1 or 2, wherein the lipid further comprises a steroid selected from the following classes of steroids: cholestane, coran, pregnane, androstan or estane; or a phosphoglyceride selected from the group comprising phosphatidylcholine, phosphatidylglycerol, or phosphatidylethanolamine; or a lipid selected from the group comprising two or more combinations thereof.

14. The pharmaceutical composition according to claim 1 or 2, wherein the lipid further comprises a phospholipid selected from dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), or lecithin, or a combination of two or more thereof.

15. The pharmaceutical composition according to claim 1 or 2, wherein the sugar comprises mannitol or trehalose, and the lipid comprises cholesterol.

16. The pharmaceutical composition according to claim 1 or 2, wherein the weight percentage of the components relative to the total weight of the composition is within the following ranges: API 50 to 99.5 wt%; sugar 0.5 to 45 wt%; and lipid 0.01 to 5 wt%.

17. The pharmaceutical composition according to claim 1 or 2, wherein the weight percentage of the components relative to the total weight of the composition is within the following ranges: API 80 to 99.5 wt%; sugar 0.5 to 20 wt%; and lipid 0.04 to 2 wt%.

18. The pharmaceutical composition according to claim 1 or 2, wherein the API is present in an amount of 30 wt% or more based on the total weight of the composition.

19. The pharmaceutical composition according to claim 1 or 2, wherein the API is present in an amount of 50 wt% or more based on the total weight of the composition.

20. The pharmaceutical composition according to claim 1 or 2, wherein the composition is a high-dose inhalation composition that provides an API with a single inhalation dose of at least 2.5 mg or more.

21. A pharmaceutical composition according to claim 1 or 2 for use as a pharmaceutical.

22. The pharmaceutical composition according to claim 21 for use in the treatment of a patient's lung condition.

23. A dry powder inhaler containing the pharmaceutical composition described in claim 1.

24. A single-use inhaler, the dry powder inhaler according to claim 23.

25. A dry powder inhaler according to claim 23 or 24, comprising a mouthpiece, an inhaler body, and a cartridge for receiving the aforementioned dose.

26. The dry powder inhaler according to claim 23 or 24, wherein the cartridge can be moved relative to the inhaler body in order to enable administration via the mouthpiece.

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

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

29. A method for producing the pharmaceutical composition described in claim 1 or 2, a. A step of combining the API with one or more excipients, each containing at least one sugar or at least one lipid, or both at least one sugar and at least one lipid, and forming a homogeneous powder. b. A step of reducing the particle size distribution of the compound, The above composition is prepared by co-grinding, and the lipids include cholesterol.

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

31. The method according to claim 29, wherein step (b) includes jet mill grinding.

32. The method according to claim 29, 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 obtained pharmaceutical composition and jet-milled together to produce a pharmaceutical composition comprising the API, at least one sugar and at least one lipid.

33. The method according to claim 29, wherein the injection pressure of the jet mill grinding step is 2 to 12 bar.

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

35. The method according to claim 29, wherein the temperature in the size reduction step is 60°C or less.

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

37. The method according to claim 29, wherein the temperature in the size reduction step is 20°C or higher.

38. The method according to claim 29, wherein no conditioning step is used, or a reduced amount of conditioning time is used compared to the conditioning time required to condition a composition comprising micronized API alone.

Images