Pharmaceutical composition for dry powder inhaler of coated crystalline form dry powder for inhalation

Abstract

The present invention describes a pharmaceutical composition for a dry powder inhaler comprising one or more active pharmaceutical ingredients (APIs) coated with one or more force control agents (FCAs), wherein the crystalline form of the API particles is micronized to an inhalable range and the particles are coated with a force control agent, thereby optimizing the aerodynamic performance. The present invention also describes a method for manufacturing the pharmaceutical composition and its use in medicine.

Description

Detailed Description of the Invention

[0001] [Technical Field of the Invention] The present invention generally relates to inhalable powders and methods for making them, and more particularly to pharmaceutical compositions for dry powder inhalers comprising one or more active pharmaceutical ingredients (APIs) coated with one or more force control agents (FCAs). The present invention also relates to a method for producing a dry powder inhaled pharmaceutical composition having optimized aerodynamic performance by micronizing API particles to an inhalable range and coating the particles with a force control agent. More specifically, it relates to a micronization method for producing a liquid mixture containing suspended API and dissolved FCA, and then spray-drying the micronized API particles coated with FCA. The produced pharmaceutical composition can be applied in the pharmaceutical field, more specifically, to inhalable powders with a high drug loading or insoluble active ingredients.

[0002] A dry powder inhaler (DPI) is a commonly used delivery system for pulmonary administration of an active pharmaceutical ingredient (API) for the treatment of diseases such as asthma or chronic obstructive pulmonary disease. Most DPIs have been developed as carrier-based mixtures in which a coarse inert carrier is mixed with micronized drug particles of an inhalable particle size (less than 5 μm). Addition of excipients to micronized crystalline forms of API by solid mixing is efficient in improving the aerodynamic performance for low API loadings, but since the excipient-API interaction is saturated, API-API interactions cause issues with aerodynamic performance. Dry powder formulations without an inhaled carrier are also a popular solution for delivery of the active ingredient to the lungs. Nevertheless, very recently, high API loading formulations have received significant attention for acute respiratory treatments such as antibiotics, antivirals, or vaccines. Delivery of high API loadings to the lungs can be achieved by formulations containing a high percentage of API with good aerodynamic performance. Such solutions with high drug loadings are typically characterized by powders with high adhesiveness and stickiness due to a small median particle size (large surface area), and thus, added excipients need to function efficiently to promote particle dispersion upon actuation. Particle engineering by spray drying of high loading formulations from solution can result in good performance, but tends to exhibit more problematic stability due to the amorphous state of the API and excipients. Furthermore, amorphous API can result in faster API release which may not be appropriate for certain treatments.

[0003] Accordingly, the inventors recognized that high loading formulations containing crystalline forms of API and an efficient low dosage of excipients (by coating the API surface) enable the development of new products and more effective treatments thereby.

[0004] The inventors found that the most relevant obstacle in developing such formulations is typically to overcome the interparticle forces between the micronized drug particles, which are typically highly adhesive and result in low aerosolization performance. The present invention seeks to address this problem.

[0005] It is known to introduce a force control agent (FCA) onto the surface of API particles by impact methods, such as mechanofusion. This is an energy-intensive dry coating method designed to fuse the FCA around the API surface (Begat et al., The Role of Force Control Agents in High-Dose Dry Powder Inhaler Formulations, Journal of Pharmaceutical Sciences, Vol. 98, No. 8, August 2009; Begat, P and Price, R., The Influence of Force Control Agents on the Cohesive-Adhesive Balance in Dry Powder Inhaler Formulations). In this method, the particles are subjected to high shear forces and highly localized compressive forces.

[0006] An impact method for the preparation of a formulation in which an active pharmaceutical ingredient (API) is combined with an FCA is disclosed below.

[0007] U.S. Patent No. 11103448 and U.S. Patent Application Publication No. 20160158150 relate to methods of including an additive (such as leucine as a force control agent) in a formulation by co-jet milling with API particles. Milling is also described in U.S. Patent No. 10022303, where the force control agent (or adjuvant) can be part of a crushable matrix that can be milled in a dry milling process, or an adjuvant (such as leucine) is added to the particles at the end of dry milling and then further processed by mechanofusion, cyclomixing, or high-pressure homogenization. U.S. Patent No. 8303991, U.S. Patent No. 895661, and U.S. Patent No. 9931304 also describe methods of combining an additive (or FCA) with an API by milling to produce composite particles in which the FCA is preferably in the form of a coating.

[0008] Compared to these methods that can result in uncontrolled particle modification, the present invention enables more precise control of the particle size distribution without inducing polymorphic modification or chemical decomposition of the API between both micronization and coating with FCA. Further, by dissolving the FCA in solution, the present invention enables a more controlled and uniform deposition of the agent onto the API particle surface, potentially resulting in improved coating uniformity. Methods for reducing the controlled particle diameter into a narrow distribution by wet milling followed by isolation of the powder by spray drying are described in U.S. Patent No. 9,956,144. A preferred aspect of the present invention is that the method claimed herein results in the production of API particles encapsulated with FCA, particularly aimed at improving the aerosolization performance of the powder.

[0009] The Spanish Patent No. 2,548,884 relates to a method for preparing glycopyrrolate particles combined with FCA. The described method relates to milling by mechanofusion, cyclomixing, impact milling, or high-pressure homogenization. The present invention has the advantage of including a more controlled and smooth micronization step of the active ingredient, followed by surface coating with FCA by spray drying, which is an innovative aspect compared to the above-mentioned patent.

[0010] The production of composite particles by spray drying is widely known. Methods for producing encapsulated API particles including a spray drying step are disclosed below.

[0011] U.S. Patent No. 8,668,934 describes a method that includes two different solvents in which an API and an excipient (an amino acid or a phospholipid) have differentiated solubility (the excipient is soluble in a more polar first solvent while the API is soluble in a less polar second solvent), and then spray drying to isolate composite particles. The same patent describes a formulation that includes an API and an excipient that at least partially encapsulates the API, where the excipient is more water-soluble than the API. Japanese Patent Publication No. 695,341 relates to a method of solubilizing a lipophilic drug in a terpene, then adding a functional excipient (such as leucine) to water to form a final emulsion, which is then spray dried to isolate a dry powder.

[0012] An important aspect of the invention described herein, unlike the patents described above, is that the active ingredient is not spray dried in a liquid state, which means that when the API is spray dried, its crystalline state is maintained and an amorphization process typical of spray drying methods does not occur. Thus, since amorphous products tend to crystallize, the pharmaceutical composition provided by the present invention exhibits higher physical stability. Compared to the methods described above, the method described in the present invention also has the advantage that it allows for the operation using a single solvent for micronization and API encapsulation steps, resulting in a more efficient and economical method.

[0013] JP 2011-1019970 A and WO 2004 / 093848 describe DPI devices containing composite particles comprising FCA to improve the aerosolization performance of the active ingredient. Unlike the invention described herein, these documents do not describe strategies for achieving controlled micronization of the API while maintaining its crystal form or surface coating of the active particles with FCA. Further, these applications describe co-spray drying of a force control agent and an active ingredient already described previously (e.g., U.S. Patent No. 8,668,934). In these cases, both the active ingredient and the excipient are dissolved in the process solvent. However, in the present method, the active ingredient is not dissolved but is suspended in a poor solvent while the FCA is dissolved therein. The inventors have found that this results in particles having an active ingredient micronized in crystalline form and coated with a force control agent, having improved aerodynamic performance and stability.

[0014] WO 2005 / 025535 relates to a method for producing composite particles by spray drying a solution or suspension comprising an API and an FCA. A preferred embodiment of the present invention is that the method described herein involves controlled micronization of the API in crystalline form to achieve a tailored particle size suitable for drug delivery to the target region of the lung.

[0015] From the above prior art, no method has been described for effectively solving the problem of producing a high-dose DPI formulation by encapsulating API particles in crystalline form with FCA.

[0016] [The Invention] According to one aspect, the present invention provides a pharmaceutical composition suitable for a dry powder inhaler, the pharmaceutical composition comprising particles comprising one or more micronized crystalline active ingredients (API) coated with one or more force control agents (FCA). The composition is suitably an inhalable powder, for example a dry powder.

[0017] The composition typically includes a population of particles, whereby it is understood that the population of particles has a measurable particle size distribution. The particle size of the particles containing one or more micronized crystalline forms of the API is suitable, for example, for inhalation by a dry powder inhaler (DPI).

[0018] In a further aspect, the present invention is a method for manufacturing a pharmaceutical composition suitable for a dry powder inhaler according to the invention as claimed and described herein, comprising a. reducing the particle size distribution of the composition to obtain one or more APIs in a micronized crystalline form having a desired particle size distribution suspended in a poor solvent system; b. adding one or more FCAs soluble in the poor solvent system to provide a mixture of the poor solvent in which the FCA is dissolved and the micronized API in the suspension; c. removing the poor solvent from the mixture by spray drying to obtain a coating of the micronized crystalline form of the API with the dissolved FCA and provides a method.

[0019] The step of adding one or more FCAs soluble in the poor solvent system may be carried out before or after, or both before and after, the reducing step. In a preferred embodiment, the step of reducing the particle size distribution of the composition to obtain one or more APIs in a micronized crystalline form preferably includes wet milling a suspension of the crystalline form API by techniques such as microfluidization or high-pressure homogenization. Preferably, jet milling is not used.

[0020] The present invention also provides a pharmaceutical composition comprising micronized coated API particles obtained or obtainable by the method according to the invention as claimed and described herein.

[0021] Accordingly, the present invention provides a method as described and a pharmaceutical composition produced according to such a method, wherein during the method, the active ingredient (API) is suspended rather than dissolved in the poor solvent, while one or more force control agents (FCA) are dissolved in the poor solvent. Under these conditions, the mixture can be wet-milled, for example, using microfluidization or high-pressure homogenization, as described herein, to reduce the particle size distribution of the API. Thereafter, the mixture is spray-dried under these conditions, i.e., under the conditions that the API is suspended in the poor solvent while one or more force control agents (FCA) are dissolved in the poor solvent.

[0022] In a further aspect, a pharmaceutical composition in the form of an inhalable dry powder, the composition comprising particles comprising one or more micronized crystalline forms of an active ingredient (API) coated with one or more force control agents (FCA), is also provided, wherein the inhalable powder is obtained by wet grinding comprising a wet milling step and a spray drying step. The wet milling step preferably comprises microfluidization or high-pressure homogenization. Suitably, the wet milling step is carried out with a suspension of the API, for example a suspension of the crystalline form of the API in a poor solvent. This may be, for example, an aqueous system, such as water. One or more FCAs may be dissolved in the poor solvent prior to the wet milling step (i.e., the poor solvent for the API functions as the solvent for the FCA). Alternatively, one or more FCAs may be dissolved in the poor solvent after the wet milling step.

[0023] In a further aspect, there is provided a pharmaceutical composition in the form of an inhalable dry powder, the composition comprising particles comprising one or more micronized crystalline forms of an active pharmaceutical ingredient (API) coated with one or more force control agents (FCA), the coated particles being obtained by adding the one or more force control agents (FCA) to a wet milled crystalline suspension of the API prior to spray drying. The wet milled crystalline suspension is preferably prepared by microfluidization or high pressure homogenization. Suitably, the wet milling step is carried out on a suspension of the API, for example a suspension of the crystalline form of the API in a poor solvent. This may be, for example, an aqueous system, for example water. The one or more FCA may be dissolved in the poor solvent prior to the wet milling step (i.e., the poor solvent for the API functions as the solvent for the FCA). Alternatively, the one or more FCA may be dissolved in the poor solvent after the wet milling step. The resulting mixture may then be spray dried.

[0024] Thus, the coated particles of the present invention comprise a coating formed on the API particles by wet milling a suspension of the crystalline form of the API in a poor solvent in which the force control agent (FCA) is dissolved. Preferably, the coating formed on the API particles is substantially uniform.

[0025] In a further aspect, the present invention also provides a dry powder inhaler comprising the pharmaceutical composition of the present invention as claimed and described herein.

[0026] In a further aspect, the present invention also provides the pharmaceutical composition of the present invention as claimed and described herein for use as a medicament. For example, for use in the treatment of pulmonary diseases in human or animal patients. Administration of the medicament may be by any suitable means, but is preferably by dry powder inhaler.

[0027] The present invention describes a pharmaceutical composition for a dry powder inhaler comprising one or more active pharmaceutical ingredients (APIs) coated with one or more force control agents (FCAs). The one or more APIs are in crystalline form. The present invention also describes a method for producing a high-dose dry powder formulation of an inhalable crystalline form with optimized aerodynamic performance by coating the API micronized to an inhalable range with a force control agent when spray drying a suspension of the API in which the force control agent is dissolved. The present invention addresses the undesirable results of formulations of aerosolized API alone, specifically the highly variable and low performance due to strong API-API interactions.

[0028] In one aspect, the API excludes crystalline N-{3-[(lS)-l-{[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino}ethyl]phenyl}-5-methylpyridine-3-carboxamide (Compound X). In another aspect, the pharmaceutical composition excludes a pharmaceutical composition comprising crystalline Compound X (especially Form A) and leucine, or crystalline Compound X (especially Form A) and L-leucine, or crystalline Compound X (especially Form A) and lactose. More specifically, the pharmaceutical composition excludes a pharmaceutical composition produced by spray drying a composition comprising 31.4 g of crystalline Compound X and 0.628 g of L-leucine, or a pharmaceutical composition produced by spray drying a composition comprising 31.0 g of crystalline Compound X and 1.861 g of L-leucine, or a pharmaceutical composition produced by spray drying a composition comprising 31.5 g of crystalline Compound X and 3.152 g of L-leucine. Also more specifically, the pharmaceutical composition may exclude a pharmaceutical composition comprising 96% of Form A of crystalline Compound X and 4% leucine (by weight). Also more specifically, the pharmaceutical composition excludes a pharmaceutical composition produced by spray drying a composition comprising 249 g of crystalline Compound X and 5.0 g of leucine, or a pharmaceutical composition produced by spray drying a composition comprising 230 g of crystalline Compound X and 4.9 g of leucine. More specifically, the pharmaceutical composition may also exclude a pharmaceutical composition formed by mixing 0.14 kg of L-leucine with a micronized suspension (5% w / w / suspension) of 1.86 kg of compound X in crystalline form in water in form B and spray-drying the mixture.

Brief Description of the Drawings

[0029]

Figure 1

Figure 2

Figure 3A

Figure 3B

[0030] [Detailed Description of the Invention] One aspect of the present invention is a dry powder pharmaceutical composition of an active ingredient (API) coated with a force control agent (FCA). The pharmaceutical composition may also include two or more excipients used for formulating the API as a bulk intermediate drug product. Another aspect of the present invention is a formulation of an API coated with a force control agent, wherein the particles containing the API and the FCA have a particle size distribution within the inhalation range. As used herein, the "inhalation range" is the particle size range predicted to ensure delivery of the formulated particles to the surface of the airway. Preferably, it is a particle size distribution with Dv90 less than 10 μm. Most preferably, it is a particle size distribution with Dv90 less than 6 μm.

[0031] The present invention is applicable to all drugs in crystalline form that are insoluble in a solvent in which the force control agent is soluble. Examples include, together with an amino acid (water-soluble) as the force control agent, water-insoluble APIs (for example, corticosteroids, for example fluticasone furoate, poorly soluble antibiotics, antifungal agents, for example itraconazole, poorly soluble antiviral agents, for example remdesivir, anthelmintics, for example ivermectin). These examples are presented herein.

[0032] As used herein, the term "force control agent" (FCA) refers to a compound exhibiting anti-adhesion and / or anti-friction properties, such as an amino acid or derivative (for example, L-leucine, tri-leucine, arginine, alanine), a phospholipid (for example, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), lecithin, or a fatty acid derivative (for example, magnesium stearate).

[0033] As discussed herein, the terms Dv10, Dv50, and Dv90 are known to those skilled in the art. Dv50 refers to the maximum particle diameter below which 50% of the sample volume is present. Dv90 refers to the maximum particle diameter below which 90% of the sample volume is present. Dv10 refers to the maximum particle diameter below which 10% of the sample volume is present.

[0034] One aspect of the present invention is a dry powder pharmaceutical composition of an API coated with a force control agent that shows an increase in the fine particle fraction when compared to the micronized API alone. The product of interest in the present invention may be a formulation of an API coated with a force control agent that has a lower aerodynamic mass median diameter, for example, compared to micronized API alone not coated with FCA.

[0035] As discussed herein, the terms "fine particle fraction" and "aerodynamic mass median diameter" are known to those skilled in the art. The "fine particle fraction" refers to the fraction of API having an aerodynamic particle diameter of less than 5 μm. The "aerodynamic mass median diameter" refers to the diameter at which 50 mass % of the aerosol particles are larger and 50 mass % are smaller. As discussed herein, the term "aerodynamic particle diameter" refers to the diameter of a spherical particle having a density of 1 cm-3 that settles in still air at the same velocity as the particle in question. This diameter is obtained by an aerodynamic classifier, such as a cascade impactor.

[0036] One aspect of the invention is a dry powder pharmaceutical composition comprising one or more APIs and one or more excipients, such as one or more FCAs, and these components may be present in any suitable amounts. Preferably, in one example, the one or more FCAs are present at a concentration of 30% w / w or less, preferably 15% w / w or less, most preferably 10% w / w or less (based on the mass of the API component).

[0037] The invention also describes a new manufacturing method for producing a formulation for a dry powder inhaler having a controlled aerodynamic particle size distribution, comprising one or more APIs and one or more excipients / FCAs, the method comprising the steps described herein.

[0038] In a preferred aspect, the population of particles comprising the pharmaceutical composition of the invention described herein has a particle size range with a Dv90 of 10 μm or less. In one example, the particle size range may be such that the Dv90 is 6 μm or less.

[0039] In a preferred aspect, there is provided a pharmaceutical composition of the invention described herein, wherein particles comprising one or more APIs in their micronized crystalline form coated with one or more FCAs have a higher fine particle fraction (FPF) compared to a pharmaceutical composition comprising the same micronized particles but no FCAs. In one aspect, the fine particle fraction (FPF) may be 30% or more of the released dose when testing a capsule containing the composition in a dry powder inhaler.

[0040] In a further aspect, there is provided a pharmaceutical composition of the present invention, wherein particles comprising one or more APIs in their micronized crystalline form coated with one or more FCAs have reduced variability with respect to fine particle fraction (FPF) when compared to a pharmaceutical composition comprising the same micronized particles but no FCAs. This reduced variability can be measured and evaluated, for example, by considering the relative standard deviation (RSD) applied to the FPF measurement. The present invention provides a significantly greater consistency of FPF.

[0041] In a preferred aspect of the present invention, the one or more FCAs can be any suitable agent that exhibits anti - adhesion and / or anti - friction properties in a formulation comprising one or more APIs. Suitably, the FCA may be selected from the group comprising leucine (i.e., L - leucine, isoleucine, tri - leucine), distearoyl phosphatidylcholine (DSPC), dipalmitoyl phosphatidylcholine (DPPC), alanine, lecithin, arginine, histidine, lysine, valine, or stearates such as magnesium stearate, or a combination of two or more thereof.

[0042] The FCA may be a phosphoglyceride selected from the group comprising phosphatidylcholine, phosphatidylglycerol, or phosphatidylethanolamine, or a combination of two or more thereof.

[0043] The FCA may be, for example, dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), dimyristoyl phosphatidylcholine (DMPC), or lecithin, or a combination of two or more thereof.

[0044] In a preferred embodiment of the present invention, one or more APIs used in the pharmaceutical composition are APIs in a crystalline form that is insoluble in a solvent in which the FCA used in the composition is soluble. The one or more APIs may include an API, such as a corticosteroid, such as fluticasone propionate and budesonide, a long-acting β-adrenergic receptor agonist (LABA), such as indacaterol, vilanterol, salmeterol, and formoterol, a short-acting β2-adrenergic receptor agonist (SABA), such as albuterol, a long-acting inhaled muscarinic antagonist (LAMA), such as acridinium bromide, an antipsychotic, such as loxapine, an antiparkinson drug, such as levodopa, an antibiotic, such as tobramycin, an antifungal drug, such as itraconazole, or an antiviral drug, such as remdesivir and laninamivir, or an anthelmintic drug, such as ivermectin.

[0045] In one embodiment of the present invention, one or more FCAs are present in an amount of FCA of 30% by weight or less (in total) per weight of the total API. In one example, this amount may be 15% wFCA / wAPI or less, or 10% wFCA / wAPI or less. In a preferred embodiment, the amount of FCA is at least 5% or more, or at least 7% or more per weight of the total API. A preferred range may be, for example, 5% to 20%, or 7% to 15% per weight of the total API. The amount required to obtain the desired result can vary to some extent depending on the API, and in some cases, an amount of FCA ranging up to 50% per weight of the total API, such as 25% to 50%, may be used.

[0046] In the present invention, the particles of one or more APIs are not simply mixed with one or more FCAs, but are densely coated with FCA, as schematically illustrated in FIG. 1, for example. Appropriately, each particle in the population of particles has a coating of FCA.

[0047] In the method of the present invention, the step of reducing the particle size distribution is used to obtain a micronized crystalline form of the API having the desired or target particle size distribution, and preferably includes subjecting the particles to a wet milling step. This may include, for example, one or more of high-pressure homogenization, microfluidization, ball mill grinding, high-shear mixing, or any combination thereof. High-pressure homogenization and microfluidization are particularly preferred. As shown above, in a preferred embodiment, the population of particles comprising the pharmaceutical composition of the present invention described herein has a particle size range with Dv90 of 10 μm or less, or may be such that Dv90 is 6 μm or less.

[0048] Preferably, one or more APIs remain in the crystalline state through the method of the present invention. Suitably, one or more APIs are provided as a liquid suspension prior to drying.

[0049] In a preferred embodiment, the step of reducing the particle size distribution includes the use of high-pressure homogenization or microfluidization with a solvent system in which one or more APIs are insoluble. That is, the API is in suspension, and suitably, the step of reducing the particle size distribution is carried out with a suspension of the crystalline form of the API.

[0050] The temperature used in the step of reducing the particle size distribution is preferably about 60 °C or less, but may be about 10 °C or less depending on the API and the intensity of the method used. Temperatures within this range may be used. For example, the temperature of the step of reducing the particle size distribution may be about 20 °C or more, but is still preferably less than 60 °C.

[0051] The pressure used during the step of reducing the particle size distribution is also considered. Preferably, the pressure in the step of reducing the particle size distribution is about 100 bar or less, although it may be about 50 bar or less. Pressures within this range may be used. For example, the pressure used in the step of reducing the particle size distribution may be about 10 bar or more, although in one aspect it is still preferably less than 100 bar. However, in some methods, the pressure in the step of reducing the particle size distribution may be 100 bar or more.

[0052] In the method of the present invention, preferably, the poor solvent system comprises only one (i.e., a single) poor solvent. Since the characteristics of the API suspension are important for the present invention, as used herein, the term poor solvent relates to one or more APIs. Suitably, the poor solvent is a solvent for one or more FCAs. The use of a single solvent is a particular advantage of the method and does not require multiple or different solvents. In one preferred aspect, a single solvent is used in which one or more APIs are insoluble and one or more FCAs are soluble. This may be the case, for example, for all steps of the method, i.e., steps (a), (b), and (c) described and claimed herein. A poor solvent or poor solvent system is a solvent or solvent system in which the API is insoluble. For example, less than 1% (by weight) of the API dissolves in the poor solvent. Suitable poor solvents will be apparent to those skilled in the art depending on what the API is.

[0053] Any suitable poor solvent system may be used, although preferably the poor solvent system is selected from the group comprising water, ethanol, methylene chloride, methanol, and other alcohols such as C3, C4, or C5 aliphatic alcohols, ketones, and polar protic solvents. The ketone solvent may include, for example, acetone, methyl ethyl ketone, or methyl isobutyl ketone. An aqueous system, particularly one containing water, is preferred. This works well for APIs that are insoluble in water or polar solvents.

[0054] In the method of the present invention, suitably, the total solids (referring to both insoluble solids and soluble solids) in the lean solvent is about 20% by weight or less, preferably 15% by weight or less, and most preferably 10% by weight or less.

[0055] In the step of reducing the particle size distribution, for example, when micronization chambers are used in cases where microfluidization is employed, these preferably have an inner diameter of less than 500 μm, preferably less than 200 μm, and most preferably less than 150 μm.

[0056] The method of the present invention includes the step of removing the lean solvent from the mixture by spray drying to obtain a coating of the micronized crystalline form of the API with the dissolved FCA. Spray drying suitably includes spray drying of a suspension of one or more APIs. This enables the maintenance of the crystalline form and is particularly beneficial.

[0057] As will be appreciated, the pharmaceutical compositions described and claimed herein are suitable for use as medicaments. For example, a pharmaceutical composition of the present invention for use in the treatment of a patient's lung disease may be provided. Suitably, such a composition may be administered by a dry powder inhaler.

[0058] When a dry powder inhaler is used, this may be, for example, a disposable inhaler. A suitable dry powder inhaler may include a mouthpiece, an inhaler body, and a cartridge for containing a dose of the pharmaceutical composition of the present invention described and claimed herein. For example, the cartridge may be movable relative to the inhaler body to make the dose available through the mouthpiece. In one aspect, the cartridge may include one reservoir or multiple reservoirs. Each reservoir may provide, for example, a single dose.

[0059] It is understood that the present invention also provides, accordingly, a dry powder inhaler comprising the pharmaceutical composition of the present invention described and claimed herein.

[0060] In one aspect, the present invention can be carried out, for example, by preparing a suspension of a coarse hydrophobic API in water, mixing it until a uniform suspension is obtained, and then performing high-shear mixing for an appropriate time, for example, 1 hour. Optionally, one or more force control agents may also be added at this stage, or may be added later as described below (or may be added at both stages). When added at this stage, the force control agent can be mixed so that the API remains in the suspension to obtain a solution of the force control agent in a poor solvent. The particle size of the suspended API can be reduced, for example, by high-pressure homogenization at a pressure of, for example, 50 bar for 20 cycles in a 200 μm chamber, plus 10 cycles in 100 μm and 200 μm chambers, while ensuring a uniform suspension. Thus, in one aspect of the present invention, the API and one or more FCAs may be subjected together to the step of reducing the particle size distribution of the composition. Alternatively, or additionally, one or more FCAs may be added after the step of reducing the particle size distribution of the composition. The high-pressure homogenization method reduces the particle size by passing the liquid through a narrow gap under high pressure, where different processing parameters, such as pressure, solid concentration, and number of cycles, result in changes in the particle size. A force control agent, such as L-leucine, is added to the suspension, and the mixture is stirred until the L-leucine is fully dissolved. L-leucine can be added twice through drying to achieve L-leucine contents of 0%, 5%, and 15%. For each addition of L-leucine, the suspension can be stirred for at least 30 minutes to completely dissolve it. The mixture of API, L-leucine, and water is spray-dried with stirring in an open-loop setting, for example, at a feed rate of 10 g / min, an outlet drying temperature of, for example, 75 °C, an inlet temperature of, for example, 135 - 150 °C, and a rotameter set to, for example, 50 mm for the atomization flow rate. The spray dryer can be equipped with, for example, a two-fluid nozzle having a 2.2 mm cap and a 1.5 mm hole, and a high-performance cyclone. For example, an amount of about 30 mg of the resulting composition is filled into size 3 HPMC capsules that are immediately actuated using a DPI device.

[0061] "Error! Reference source not found." is a method comprising: (i) a step of reducing the particle size of an API, in which micronized API having a target particle size distribution is obtained and suspended in a poor solvent system; (ii) a step of adding a force control agent (FCA) soluble in the solvent system used, resulting in a mixture of a solvent, micronized API in suspension, and dissolved FCA; and (iii) a step of removing the solvent from the mixture by spray drying, resulting in a coating of the micronized API with the dissolved FCA. A schematic of the method is shown.

[0062] The step of reducing the particle size carried out in step (i) of the method of the present invention can be any suitable step of reducing the particle size. Such methods are known to those skilled in the art. Preferably, step (i) of reducing the size is carried out by high-pressure homogenization, microfluidization, ball mill grinding, high-shear mixing, or any combination thereof. Most preferably, step (i) of reducing the size is carried out by high-pressure homogenization or microfluidization. Preferably, jet milling is not used. The inventors have found that this is too strong and can potentially be disadvantageous, resulting in the formation of some amorphous material. In particular, the method of the present invention using wet milling techniques, such as high-pressure homogenization or microfluidization, makes it possible to maintain the crystalline form of the API throughout the method.

[0063] The solvent system used is a poor solvent for at least one API, and at least one excipient (one or more FCAs) dissolves or partially dissolves therein. As used herein, the term "poor solvent" describes a solvent or solvent system in which a substance is substantially insoluble and thus, when the substance is mixed with its poor solvent, the substance is suspended therein as opposed to being dissolved in the poor solvent. Preferably, the term is used to refer to a solvent or solvent system in which the substance is completely insoluble. What is regarded as a poor solvent for a particular substance is generally known to those skilled in the art. Typical solvents are, for example, water and ethanol for treating one or more APIs with, for example, an FCA, such as L-leucine. In these cases, the solvents in which the API is insoluble are water and ethanol. Other solvents include ketones, methylene chloride, methanol, and other alcohols, such as polar protic solvents or alcohols, and are suitable for treating one or more APIs with, for example, DSPC.

[0064] Certain specific embodiments and implementations of the present invention are described in more detail with reference to the following examples. Example 1 is presented to aid in the understanding of the present invention but is not intended to limit its scope in any way and should not be regarded as limiting its scope.

[0065] The formulations of the examples of the present invention included one or more of the following materials.

[0066] Remdesivir Leucine Distearoylphosphatidylcholine (DSPC) Lecithin Fluticasone furoate The formulations of the examples of the present invention were characterized by the following techniques.

[0067] Laser diffraction equipment was used for measuring the particle size distribution of the suspension.

[0068] A laser diffraction instrument combined with a Rodos drying and dispersion unit and an Aspiros module (Sympatec GmbH, Germany) was used for measuring the particle size distribution of the formulation. (Using an R2 lens (0.45 - 87.5 μm) with a focal length of 50 mm) A dispersion pressure of 0.1 bar, and (using an R1 lens (0.18 - 35 μm) with a focal length of 20 mm) pressures of 5 bar (Example 1), 4 bar (Example 2 - Test 1), and 2.5 bar (Example 2 - Test 2) were applied to determine the size of either agglomerates or single particles, respectively. The speed was maintained at 50 mm / s.

[0069] Size 3 capsules of hydroxypropyl methylcellulose (HPMC) containing 30 mg ± 1.5 mg of powder (Capsugel, Colmar, France) were used for all in vitro aerosolization studies. The materials of Example 1 were tested in a Next Generation Impactor (NGI) (Copley Scientific, Nottingham, UK) equipped with a pre-separator connected to a vacuum pump (Copley Scientific, Nottingham, UK). The NGI cups were coated with a 1% glycerol (v / v) solution in 1 mL of ethanol. 15 ml of dissolution medium was placed in the pre-separator. Each test consisted of 1 actuation of the capsule into the NGI using a DPI device at either 60 L / min or 100 L / min for either 4 s or 2.4 s. The API content deposited at each stage was recovered and analyzed by HPLC, enabling the determination of ED and FPD and the distribution between stages, and ensuring a mass balance of the recovered material with an error of less than 15%. All aerodynamic performance experiments were performed 3 times. The materials of Example 2 were tested by a Weight Fast Screening Impactor (FSI). Each test consisted of 1 actuation of the capsule into the FSI equipped with a USP induction port and a pre-separator (Copley Scientific, Nottingham, UK) using a DPI device at 100 L / min for 2.4 s. The FSI filters were weighed before and after capsule actuation, and the fine particle dose (of the API) was calculated by correcting the amount of powder retained on the filter by this difference and the determined analytical result (% w / w) value. The combined device and capsule were also weighed before and after actuation to determine the non-release fraction. The experiments were performed 3 times.

[0070] The powder X-ray diffraction (XRPD) pattern was obtained by a PANalytical (Malvern, UK) X’Pert PRO X-ray diffraction system using Cu K radiation (λ = 1.54 Å). The voltage and current intensity of the generator were set at 45 kV and 40 mA, respectively, and the 2θ scanning range was 4° to 40° with a step size of 0.0131303° and a counting time of 99.450 s per step. The sample was loaded using zero-background technology.

[0071] A pharmaceutical composition comprising micronized coated API particles according to the invention or obtained according to the method of the invention can be used as a medicament in the treatment of a patient's lung disease. Such treatment can include administration by a dry powder inhaler. The pharmaceutical composition of the invention can be delivered by a dry powder inhaler, such as a disposable inhaler. The inhaler can include a mouthpiece, an inhaler body, and a cartridge for containing the dose, and the cartridge can be movable relative to the inhaler body to make the dose available through the mouthpiece. The cartridge of the inhaler includes one reservoir or a plurality of reservoirs, and each reservoir provides a single dose.

[0072] The present invention is particularly useful for enabling the provision of high doses of API via the inhalation route. Accordingly, the present invention provides a pharmaceutical composition as described, wherein the composition is a high-dose inhalation composition and provides a single inhalation dose of at least 2.5 mg or more of API, for example more than 5 mg or more. The high dose can also refer to the case where the amount of API in the inhaled drug dose exceeds 4% by weight of the dose (see, for example, 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; or Adhikari et al., Solid state of inhalable high dose powders, Advanced Drug Delivery Reviews. 2022, 189: 114468. doi: 10.1016 / j.addr.2022.114468). Example 1 - Changing L-leucine content in remdesivir after wet milling Remdesivir (65 g) was suspended in water (802 g), mixed until a uniform suspension was obtained, high-shear mixed for 1 hour, and fed to a laboratory-scale microfluidizer treatment device to subject the suspension to 20 cycles in a 200 μm chamber, and in addition 10 cycles in 100 μm and 200 μm chambers at a pressure of 50 bar. The following particle size results were obtained: Dv10 = 1.2 μm; Dv50 = 2.4 μm; Dv90 = 4.5 μm. After the step of reducing this particle size, the suspension was fed with stirring to a laboratory-scale spray dryer (Buchi, model B-290), and in an open-loop setting, a feed rate of 10 g / min, an outlet drying temperature of 75 °C, and an inlet temperature of 135-150 °C were used, and the rotameter was set to 50 mm for the atomization flow rate. The spray dryer was equipped with a two-fluid nozzle having a 2.2 mm cap and a 1.5 mm hole, and a high-performance cyclone. Before feeding the solution to the nozzle, the spray drying unit was stabilized with nitrogen and then with the solvent (water) to ensure stable inlet and outlet temperatures.

[0073] In this example, L-leucine was added twice to achieve L-leucine contents of 0% (Test 1), 5% (Test 2), and 15% (Test 3). For each addition of L-leucine, it was added to the remdesivir suspension and the suspension was stirred for at least 30 minutes (prior to any spray drying) to completely dissolve it.

[0074] All spray drying tests were characterized for the crystalline state of the API and L-leucine by XRPD, the geometric particle size by Malvern laser diffraction with a suitable poor solvent, and analysis by HPLC. All capsule tests were characterized for analysis by HPLC and aerodynamic performance by the Next Generation Impactor, and the weight of the deposited amount at each stage was measured by HPLC. All test capsules were tested using a PowdAir apparatus (60 L / min at 4 kPa). The capsules of Tests 1 and 3 were operated using an RS01 Plastiape (100 L / min at 4 kPa). The results are shown in Tables 1 and 2.

[0075] The spray-dried products showed analytical results of 102.9% w / w, 97.3% w / w, and 83.2% w / w, thus giving L-leucine contents calculated from the differences of 2.7% w / w and 16.8% w / w for Tests 2 and 3, respectively. Furthermore, the geometric particle size of the suspension was maintained upon spray drying, with a slight decrease in Dv90 for Test 2 (Dv90 = 4.1 μm), probably due to method variations and powder sampling. The XRPD results show that the API is maintained as a crystalline form material (no amorphous halo) and that L-leucine is in a crystalline form (crystalline form peaks are present).

[0076] These results show that the addition of different amounts of L-leucine to the suspension can be used to produce products of the desired composition. Furthermore, the addition of L-leucine does not significantly affect the particle size distribution.

[0077]

Table 1

[0078] The manufactured capsules were characterized for their aerodynamic performance by NGI as summarized in Table 2.

[0079] For the PowdAir device (flow rate of 60 L / min), the filled capsules had a fine particle fraction of 6.9 ± 1.8% of the released dose for API only, and 43.0 ± 9.2 and 37.9 ± 2.9% of the released dose for Tests 2 and 3 containing L - leucine as a force control agent. These results showed that the presence of L - leucine in the range of 2.7 - 16.8% led to an improvement in FPF of more than 4 - fold for remdesivir and the PowdAir device compared to the formulation with API only.

[0080] For the Plastiape device (flow rate of 100 L / min), the filled capsules had a fine particle fraction RSD of 76% for API only and 2.1% for Test 3 containing L - leucine as a force control agent. These results showed that the presence of L - leucine in the range of 2.7 - 16.8% led to a reduction in variability of more than 30 - fold for remdesivir and the Plastiape device compared to the formulation with API only, as L - leucine functions to make the particle - particle and particle - device interactions more uniform (e.g., reduction of energy "hot spots" of micronized particles and reduction of agglomerates).

[0081]

Table 2

[0082] All spray drying tests were characterized for the crystalline state of the API, the geometric particle size by dry dispersion (Sympatec), and analysis by HPLC. All capsule tests were characterized for analysis by HPLC and the aerodynamic performance by a Fast Screening Impactor (FSI), and the weight of the deposited amount at each stage was measured. All test capsules were tested using an RS01 Plastiape apparatus (4 kPa at 100 L / min). The results are shown in Tables 4 and 5.

[0083] The spray-dried products showed analytical results of 93.6% w / w and 93.4% w / w. The XRPD results (Figure 3) indicate that the API is maintained as a crystalline form material (no amorphous halo).

[0084] [Table 3]

[0085] [Table 4] After micronization and spray drying, the powder was filled into HPMC size 3 capsules at 20 - 25 °C and 40 ± 10% RH using an Auger filler Quantos apparatus, with a fill weight of 30 mg and a rejection limit of ±7%. The API alone was also filled into capsules for comparison purposes. The filled capsules were actuated using a Plastiape inhaler (flow rate of 100 L / min for a pressure drop of 4 kPa). The manufactured capsules were characterized for aerodynamic performance by FSI as summarized in Table 2.

[0086] From the results shown in Table 4, both FPD and FPF are improved by adding a force control agent, such as lecithin or DSPC. Comparing the results of the API alone with Tests 1 and 2, an increase in FPD of at least twofold, facilitated by the addition of the force control agent, can be observed.

[0087]

Table 5

Claims

1. A pharmaceutical composition suitable for dry powder inhalers, comprising particles containing one or more finely powdered crystalline active ingredients (APIs) coated with one or more force control agents (FCAs), The coated particles are obtained by adding one or more force control agents (FCAs) to a suspension of the wet-ground crystalline form of the API before spray drying. A pharmaceutical composition wherein the one or more APIs mentioned above consist solely of APIs in crystalline form.

2. The pharmaceutical composition according to claim 1, wherein the particle size of one or more types of micronized APIs is suitable for inhalation.

3. The pharmaceutical composition according to claim 2, wherein the suspension of the API in a wet-ground crystalline form is wet-ground by microfluidization or high-pressure homogenization.

4. The pharmaceutical composition according to claim 1 or 2, having a Dv90 of less than 10 μm in the particle size range measured by laser diffraction.

5. The pharmaceutical composition according to claim 4, having a Dv90 of less than 6 μm in the particle size range measured by laser diffraction.

6. The pharmaceutical composition according to claim 1 or 2, wherein particles containing one or more APIs in a pulverized crystalline form coated with one or more FCAs have a higher fine particle fraction (FPF) compared to a pharmaceutical composition containing the same pulverized particles but without any FCAs.

7. The pharmaceutical composition according to claim 6, wherein the particulate fraction (FPF) is 30% or more of the released dose when testing a capsule containing the composition in a dry powder inhaler.

8. The pharmaceutical composition according to claim 1 or 2, wherein the particles containing one or more APIs in a pulverized crystalline form coated with one or more FCAs have reduced variability in terms of fine particle fraction (FPF) when compared to a pharmaceutical composition containing the same pulverized particles but without any FCAs.

9. The pharmaceutical composition according to claim 1 or 2, wherein the one or more FCAs are selected from the group comprising leucine (i.e., L-leucine), isoleucine, trileucine, distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), alanine, lecithin, arginine, histidine, lysine, valine, or magnesium stearate.

10. The pharmaceutical composition according to claim 1 or 2, wherein the one or more APIs are selected from the group including APIs in crystalline form that are insoluble in a solvent in which the FCA is soluble.

11. The one or more APIs mentioned above include, for example, corticosteroids such as fluticasone propionate and budesonide; long-acting β-adrenergic receptor agonists (LABAs) such as indacaterol, vilanterol, salmeterol, and formoterol; and short-acting β-adrenergic receptor agonists such as albuterol. ２ The pharmaceutical composition according to claim 10, comprising APIs such as an adrenergic receptor agonist (SABA); a long-acting inhaled muscarinic antagonist (LAMA) such as aclidinium bromide; an antipsychotic such as roxapine; an antiparkinson's disease drug such as levodopa; an antibiotic such as tobramycin; an antifungal such as itraconazole; an antiviral such as remdesivir and laninamivir; or an anthelmintic such as ivermectin.

12. The pharmaceutical composition according to claim 1 or 2, wherein the one or more FCAs are present at a concentration of 30% wFCA / wAPI or less.

13. The pharmaceutical composition according to claim 1 or 2, wherein the one or more FCAs are present at a concentration of 15% wFCA / wAPI or less.

14. The pharmaceutical composition according to claim 1 or 2, wherein the one or more FCAs are present at a concentration of 10% wFCA / wAPI or less.

15. A method for producing a pharmaceutical composition suitable for a dry powder inhaler according to claim 1 or 2, a. A step of reducing the particle size distribution of the composition to obtain one or more types of APIs in the form of finely ground crystals having the desired particle size distribution suspended in a poor solvent system, b. A step of adding one or more types of FCA soluble in the poor solvent system before or after the step of reducing the size, or both before and after, to provide a mixture of the poor solvent in which the FCA is dissolved and the finely powdered API in the suspension, c. The step of removing the poor solvent from the mixture by spray drying to obtain a coating of the pulverized crystalline API with the dissolved FCA, Includes, A method wherein the step of reducing the particle size distribution includes subjecting the particles to high-pressure homogenization, microfluidization, ball mill grinding, high-shear mixing, or a combination thereof.

16. The method according to claim 15, wherein the step of reducing the particle size distribution includes microfluidization using a solvent system in which the one or more APIs are insoluble.

17. The method according to claim 15, wherein the step of reducing the particle size distribution includes high-pressure homogenization using a solvent system in which the one or more APIs are insoluble.

18. The method according to claim 15, wherein the temperature of the step for reducing the particle size distribution is less than 60°C.

19. The method according to claim 18, wherein the temperature of the step for reducing the particle size distribution is less than 10°C.

20. The method according to claim 15, wherein the temperature of the step for reducing the particle size distribution is greater than 20°C.

21. The method according to claim 15, wherein the pressure in the step of reducing the particle size distribution is 100 bar or more.

22. The method according to claim 15, wherein the pressure in the step of reducing the particle size distribution is less than 100 bar.

23. The method according to claim 22, wherein the pressure in the step of reducing the particle size distribution is less than 50 bar.

24. The method according to claim 22, wherein the pressure in the step of reducing the particle size distribution is greater than 10 bar.

25. The method according to claim 15, wherein the poor solvent system comprises only one poor solvent in steps (a), (b), and (c).

26. The poor solvent system includes water, ethanol, methylene chloride, methanol, and other alcohols, such as C. ３ , C ４ , or C ５ The method according to claim 15, selected from the group comprising aliphatic alcohols, ketones, and polar protic solvents.

27. The method according to claim 15, wherein the poor solvent system contains water.

28. The method according to claim 15, wherein the total solid content in the poor solvent is less than 20% by weight, preferably less than 15% by weight, and most preferably less than 10% by weight.

29. The method according to claim 15, wherein the pulverization chamber used in the step of reducing the particle size distribution has an inner diameter of less than 500 μm, preferably less than 200 μm, and most preferably less than 150 μm.

30. The method according to claim 15, wherein the spray drying includes spray drying of a suspension.

31. A pharmaceutical composition comprising micronized coated API particles obtained or obtainable by the method of claim 15.

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

33. The pharmaceutical composition according to claim 32, for use in the treatment of a patient's lung disease, including administration by a dry powder inhaler.

34. The pharmaceutical composition for use according to claim 33, wherein the inhaler is a disposable inhaler.

35. The pharmaceutical composition for use according to claim 33, wherein the dry powder inhaler comprises a mouthpiece, an inhaler body, and a cartridge for containing a dose of the pharmaceutical composition according to claim 1 or 2.

36. The pharmaceutical composition for use according to claim 35, wherein the cartridge is movable relative to the inhaler body to make the dose available through the mouthpiece.

37. The pharmaceutical composition according to claim 35, wherein the cartridge comprises one reservoir or a plurality of reservoirs.

38. The pharmaceutical composition according to claim 37, wherein each reservoir provides a single dose.

39. A dry powder inhaler comprising the pharmaceutical composition according to claim 1 or 2.

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