Inhalation composite and carrier-based formulation combination

Abstract

An inhalable pharmaceutical composition comprising: (i) spray-dried cohesive composite active particles, each composite active particle comprising an active pharmaceutical ingredient (API) material and an excipient; and (ii) carrier particles, wherein the composite active particles are mixed with the carrier particles in the form of a physical mixture. The method for preparing the pharmaceutical composition comprises the steps of: i) providing a solution of an active pharmaceutical ingredient (API) material and a solution of an excipient, which may be a separate solution or a combined solution, and spray-drying to provide cohesive composite active particles wherein each composite active particle comprises an active pharmaceutical ingredient (API) material and an excipient; ii) mixing the spray-dried, cohesive composite active particles with the carrier particles to form a physical mixture. The compositions are useful in dry powder inhalers (DPIs), in particular in depot DPI devices.

Description

[0001] The present invention relates to an inhalable pharmaceutical formulation which improves the efficiency of drug delivery by increasing the solubility of an active ingredient and / or increasing the aerodynamic performance of spray-dried particles. More particularly, it relates to a method for producing the formulation by combining spray drying and mixing unit operations. In addition, the present invention provides a solution for the processability of highly cohesive powders, such as spray-dried powders. The pharmaceutical composition can be applied in the pharmaceutical field, more specifically in high drug loading inhalable powders or insoluble active ingredients. Background of the Invention

[0003] The present invention relates to an inhalable pharmaceutical formulation which improves the efficiency of drug delivery by increasing the solubility of active ingredients and / or increasing the aerodynamic performance of spray-dried particles. More particularly, it relates to a method for producing the formulation by a combination of spray drying and mixing unit operations. In addition, the present invention provides a solution for the processability of highly cohesive powders, such as spray-dried powders. The pharmaceutical composition can be applied in the pharmaceutical field, more specifically in high drug loading inhalable powders or insoluble active ingredients.

[0004] Both carrier-based formulations and composite particles for inhalation are widespread solutions for delivering active ingredients to the lungs in powder form. Powder-based inhalers have been primarily used to treat chronic respiratory diseases, such as asthma or chronic obstructive pulmonary disease. Nevertheless, in recent years, dry powder formulations have received widespread attention in acute respiratory treatments, such as infectious diseases or vaccines. This has led to an increased interest in delivering high-payload drug compounds (such as antibiotics, antivirals, vaccines, proteins, peptides, and other drugs that can be administered systemically through the lungs) to patients. Such compositions with high drug loading are typically characterized by highly adhesive and cohesive powders due to low median particle size, and in addition low bulk density, typically at 0.1 g / cm 3 Up to 0.5g / cm 3 within the scope, especially composite engineered particles.

[0005] Therefore, we have recognized that filling these powders into devices for inhalation delivery is a major challenge given the characteristics of powders. They are often associated with long filling process times, high variability between doses, and increased challenges in selecting the filling principle. These challenges lead to time-consuming operations and lack of efficiency and reproducibility on an industrial scale.

[0006] Furthermore, we have recognized that it is a challenge to effectively atomize powders to minimize retention in devices, particularly in medium to high resistance devices such as reservoir DPI devices.

[0007] The following discussion of the prior art is intended to present the present invention in its proper technical context and allow one to properly appreciate its significance.

[0008] Pulmonary drug delivery via dry powder inhalers (DPIs) presents several advantages due to their lack of propellants, high patient compliance, high dose carrying capacity and drug stability. This has led to rapid development in recent times to realize the full potential of the lung in treating diseases locally and systemically. Nevertheless, DPIs are inherently complex and their performance depends on many aspects, including the design of the inhaler, the powder formulation and the airflow generated by the patient.

[0009] Aerosol particles inhaled from DPI show different sizes, resulting in different local lung deposition, resulting in differences in therapeutic effects. The fine particle component of aerosol is the part that produces the therapeutic effect, which is defined as the percentage of particles less than 5 μm aerodynamic diameter, or in the case of some particle size analysis instruments, is defined as the percentage of particles with a cut-off diameter close to 5 μm. Therefore, dispersion is an important consideration for the quality and efficacy of pharmaceutical aerosols. Fine particle dose (FPD) is the mass of particles with a cut-off diameter less than 5 μm in milligrams. Fine particle fraction (FPF) is the fine particle dose divided by the total emission dose.

[0010] The high cohesive properties of micronized active materials hinder the accurate metering of low doses required for inhaled drug products and make the materials difficult to handle during the manufacturing process. In order to overcome the handling and administration problems and optimize the fluidization characteristics of DPI formulations, micronized API is usually mixed with a coarse material that is easy to aerate and fluidize. For carrier-based DPI formulations, the material is usually a coarse particle portion of a sugar, such as lactose monohydrate. There are several examples in the field based on carriers, in which the micronized active ingredient is mixed with sugar (i.e. lactose).

[0011] Carrier-based formulations

[0012] US2017 / 0266122 A1 describes a pharmaceutical composition comprising composite active particles of an active substance and magnesium stearate and carrier particles for pulmonary delivery. EP 1913939 A1 describes a method for preparing particles consisting of an active ingredient and an excipient, comprising a co-grinding step and mixing the co-grinded particles with a carrier. EP1617820 B1 describes a dry powder inhaler comprising a preparation with co-grinded active ingredients and excipients (jet-milled composite particles), which are additionally attached to a carrier. These are common carrier-based preparations having a ground active ingredient combined with an excipient by dry coating and / or dry grinding. This excipient is used to reduce adhesion between the grinding particles. These disclosures are significantly different from the present invention because, compared with the present invention, the huge differences in their manufacturing methods are considered, wherein the composite particles have significantly different properties. The manufacturing process for producing composite particles disclosed in these publications is jet milling, i.e. dry milling. In contrast, the manufacturing method proposed in the present invention is spray drying, which does not involve a grinding step, which brings several advantages in terms of particle engineering. Even the ground particles in publications US2017 / 0266122 A1, EP 1913939 A1 and EP 1617820B1 are crystalline particles, which is in contrast to the amorphous spray-dried particles proposed in the present invention. The spray-dried particles proposed in the present invention have optimized and customized physicochemical properties, which present several advantages compared to ground active materials.

[0013] WO 2005 / 025536 describes a method for preparing composite active particles by jet milling active particles in the presence of additive materials. The scope of this patent application is different from that of the present invention and relates to a different method for the production of composite active particles. Compared to the production method proposed in the present invention (spray drying), this publication uses a common milling step, and as mentioned above, the significant differences between these two methods lead to significant differences in the final composite particles.

[0014] EP 2821061 A1 patent describes a dry powder formulation comprising a micronized active agent and a carrier agent, wherein fine and coarse particles of the carrier agent are used. This method is well known in the pharmaceutical industry for use in dry powder inhalers because it can significantly increase the fine particle delivery of the active material. Nevertheless, considering that these improvements are applicable to low-dose grinding particles, the examples show 0.05 to 4.5% w / w of active ingredients, and the publication is significantly different from the present invention. It is well known in the field of respiratory preparations that for carrier-based preparations, increasing the concentration of the active ingredient in the mixture leads to an increase in the number and size of individual agglomerates (agglomerates) on the surface of the lactose carrier and an increase in the number of densely packed active ingredient layers. The active ingredient present in the multilayer is not dispersed in the form of a single primary particle, but dispersed in the form of a dense agglomerate, which leads to a decrease in aerosol performance and a reduction in the fraction (fine particle fraction) deposited in the lungs.

[0015] We have recognised that carrier-based formulations therefore have disadvantages, particularly for high drug loadings (>10% w / w active material). Several studies have shown that the aerosol performance of a formulation decreases inversely as the concentration of active material in the mixture increases.

[0016] Spray dried composite particles

[0017] The vast majority of commercial DPIs rely on the use of a physical mixture of a coarse carrier (most commonly lactose monohydrate of 50-100 μm in size) with small inhalable drug particles (1-5 μm) to overcome the strong cohesiveness and adhesion of the drug and improve metering. This balance must be optimized to successfully deliver the dose deep into the lungs. Unfortunately, due to the complexity of inter-particle forces (which depends on several intrinsic and extrinsic factors), it is difficult to achieve this balance. Therefore, it has been generally accepted that only 30% of the active ingredient dose is achieved in the deep lung. In addition to the large amount of coarse carrier used, such a low ratio is a serious obstacle to the use of DPI to deliver high-dose drugs.

[0018] Over the past decade, the performance of DPIs has been significantly improved by the use of engineered drug particles through spray drying (from now on spray dried granules), carrier-free and improved excipient systems. Spray dried granules can contain only the active ingredient, or can contain the active ingredient plus at least one excipient (spray dried composite granules).

[0019] Spray drying has been explored in the inhalation field since the 1980s as an alternative method for producing fine particles with ideal flow and dispersion properties without the use of coarse carriers.

[0020] Spray drying is a tool to transform the physicochemical properties of materials to improve and optimize their aerosol performance and dissolution characteristics. Solid starting materials are dissolved in liquid media to reconstitute with well-controlled properties at the particle level (size, morphology, polymorphism, density and composition) and powder level (flowability, dispersibility and aerosolization). Several excipients have been tested in spray-dried inhalation powders for different purposes, such as bulking agents, surface modifiers and pore formers, which play a vital role in optimizing (spray-dried composite particles) aerodynamic performance and stabilizing the physicochemical properties of the particles.

[0021] Composite particles produced by spray drying, for example, are disclosed in US 7862834 B2, which describes a spray-dried pharmaceutical preparation of particles comprising an active ingredient and at least one excipient, and a method for manufacturing the particles. The particles described therein are composite particles comprising an active ingredient and an excipient that at least partially encapsulates the active agent. Considering that current production methods generally result in amorphous spray-dried particles, which means that the active substance is dispersed in at least one excipient in molecular form, both of which are in an amorphous state, the particles mentioned are significantly different from the present invention. Even more, the scope of the present invention is broader than US 7862834 B2, because it is intended to solve the processability and industrialization problems associated with the low density and high cohesiveness of spray-dried composite particles. Due to the small overall particle size of the spray-dried preparation for respiratory administration, the handling and processing of these powders are challenging. Large surface area leads to uncontrolled agglomeration and may hinder the filling process. In addition, spray-dried materials are generally low in density and low in mechanical stability, so the filling process itself may have a negative impact on the success of inhalation because the powder will be compacted and may not be well redispersed. The present invention solves or substantially reduces these problems.

[0022] Publications WO0062819 (A1), KR20010034594 A, CA2265198 (A1) and EP1925295 (A1) describe a composite formulation of an active ingredient (methacholine, histamine, nicotine or other) and sugar, which is prepared by dissolving the two components in a suitable solvent or dispersing to produce a uniform solution and drying the solution to form a powder by spray drying. No additional carrier component is disclosed, which is actually contrary to their teachings. In publication WO2021234366 A1, the composition is provided in the form of an amorphous, single-particle powder. Therefore, the particles of the powdered composition are presented as an amorphous composite of active ingredient, carrier material and optionally other ingredients. They are not physically combined by two or more discrete, independent different component particle sets, but are composed of a mixture (e.g., an ordered or interacting mixture of smaller particles of an active ingredient and a larger but independent and chemically different particle combination of a carrier material). The manufacturing process mentioned in the patent is to dissolve the API and excipients in a solvent and spray-dry the solution, which yields a molecular mixture of the API and excipients.

[0023] The development of high-dose DPIs continues to be hampered by the strong and variable interparticle forces that occur between tiny spray-dried composite particles. Such forces impede powder flow during processing and administration and lead to the formation of large, intractable aggregates that can prevent the active ingredient from reaching the lower respiratory tract, causing variable or low fine particle fractions.

[0024] The powder dispersion process in DPI is highly complex and involves several physical mechanisms, i.e., aerodynamic forces caused by air turbulence and shear flow, particle-device impacts in the inhaler body, mechanical vibrations, and particle-particle collisions. We also recognize that another point that needs improvement is the aerodynamic performance of DPI when dealing with devices (e.g., reservoirs and blister-based devices) that rely solely on turbulence generated by airflow to atomize powder. Therefore, up to now, there is no clear or optimized formulation that can be used to improve the aerodynamic performance of such devices. None of the above publications solves all the challenges associated with inhalable products that the present invention proposes to solve. These challenges include: increasing the fine particle fraction, particularly in reservoirs and / or blister-based devices, increasing solubility (in the case of poorly soluble drugs), and overcoming the difficulties associated with processability and industrialization.

[0025] Description of the invention

[0026] The present invention seeks to provide an inhalable pharmaceutical formulation comprising spray-dried cohesive composite particles physically mixed with carrier particles. The present invention proposes to improve the efficiency of drug administration by increasing the solubility of the active ingredient and / or increasing the aerodynamic performance of the spray-dried particles. The increase in solubility is achieved by the amorphous state of the spray-dried composite particles. On the other hand, the increase in aerodynamic performance is obtained by physically mixing the spray-dried composite particles with a carrier. In addition, the present invention seeks to provide a method for producing the formulation by combining spray drying and mixing unit operations. In addition, the present invention proposes a solution to the processability of highly cohesive powders, such as spray-dried powders. In addition, the present invention provides a solution to the poor aerosolization of spray-dried composite particles (especially in high resistance equipment). The pharmaceutical composition can be used in the pharmaceutical field, and more specifically can be used for high drug load inhalable powders or insoluble active ingredients for respiratory absorption.

[0027] In contrast to the disclosures of WO0062819 (A1), KR20010034594 A, CA2265198 (A1) and EP1925295 (A1), in the present invention, the composite particles (consisting of an active ingredient and at least one excipient) produced by spray drying are physically mixed with a carrier by low shear or high shear mixing after the spray drying unit operation. Therefore, the final powder properties are significantly different. In the present invention, the composite particles generally have a relatively small particle size (Dv90 below 10 μm), while the carrier particles generally have a larger particle size (Dv90>10 μm), which is in contrast to the particles described in publications WO0062819 (A1), KR20010034594 A, CA2265198 (A1) and EP1925295 (A1), wherein the composite particles of the active ingredient (methylcholine, histamine and nicotine) and the sugar (carrier) have a Dv90 below 10 μm. In addition, the preparation of the present invention has the following advantages: it is a mixture with sufficient bonding-adhesion balance between composite particles and carrier particles, so that the composite particles (including active ingredients) are released from the carrier when actuated. Therefore, the carrier remains in the throat, while the composite particles flow to the respiratory tract. In contrast, the preparations described in WO0062819 (A1), KR20010034594 A, CA2265198 (A1) and EP1925295 (A1), since these are only composite particles, the active ingredient (methylcholine, histamine, nicotine or others) will be delivered to the alveoli and lower respiratory tract of the patient together with the carrier.

[0028] In contrast to WO2021234366, the present formulation physically mixes at least two different types of particles, namely spray-dried composite active particles, preferably with a small particle size suitable for inhalation (e.g., dv90 ≤ 10 μm) and a carrier, preferably with a larger particle size, e.g., dv90 ≥ 10 μm. It is worth noting that in this field, finding suitable solvents to dissolve active ingredients and excipients is a challenge, especially when the former has poor solubility. In the method of the present invention, the composite particles are made before mixing with a carrier material (e.g., sugar), which means greater freedom in choosing a solvent. This is another advantage of the present invention.

[0029] According to one aspect of the present invention, there is provided an inhalable pharmaceutical composition comprising:

[0030] (i) spray-dried cohesive composite active particles, each composite active particle comprising an active pharmaceutical ingredient (API) material and an excipient; and,

[0031] (ii) Carrier particles

[0032] The composite active particles are mixed with the carrier particles in the form of a physical mixture.

[0033] Other aspects of the invention are described below.

[0034] The term cohesiveness / cohesiveness is well known in the field of pharmaceutical powders and is usually related to the flowability of a powder, which is often the most influential property of bulk powder behavior. Cohesiveness is a mechanism acting between particles that tends to "bind" one particle to its neighbors.

[0035] The terms "spray-dried cohesive composite active granules" and "composite active granules" are used interchangeably herein.

[0036] The carrier particles are separate and distinct from the composite active particles. Thus, there are two types of particle populations in the present invention. Once each particle population has been obtained, they are mixed or blended into a physical mixture. Thus, they are not produced jointly.

[0037] An inhalable composition is a composition suitable for administration by the inhalation route, ie capable of being inhaled through the nasal or oral passages of a patient in need thereof. Preferably, the composition is administered to the respiratory tract using a dry powder inhaler (eg a reservoir device). BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 The spray drying apparatus used is shown;

[0040] Figure 2 shows an SEM image of the spray-dried composite particles of Example 1;

[0041] Figure 3 shows the XRPD diffraction pattern of the spray-dried composite particles of Example 1;

[0042] Figure 4 shows the DSC diffraction pattern of the spray-dried composite particles of Example 1;

[0043] FIG. 5 shows the dissolution curves of the spray-dried composite particles and the jet-milled micropowder material of Example 1.

[0044] Figure 6 The X-ray powder diffraction pattern of the spray-dried composite particles obtained in Example 2 is shown.

[0045] The composite active particles used in the inhalable pharmaceutical composition of the present invention preferably have a mass median aerodynamic diameter (MMAD) equal to or less than 10 μm, more preferably less than 5 μm. The MMAD may be, for example, in the range of 1 to 10 μm, or 1 to 8 μm, or 2 to 6 μm, or 1 to 5 μm.

[0046] In one aspect, the solubility and dissolution rate of the active pharmaceutical ingredient (API) material are higher than the solubility and dissolution rate of the crystalline isolated form of the API. Solubility and dissolution rate are usually measured in an aqueous medium or solution. For example, solubility and dissolution rate can be measured in HBSS (Hank's Balanced Salt Solution). This is useful because it can be used to simulate lung fluid.

[0047] In a preferred aspect, the composite active particles comprise an active pharmaceutical ingredient (API) material in an amorphous form.

[0048] In one aspect, the composite active particles, particularly when the API is in an amorphous form, are more soluble than particles of the active pharmaceutical ingredient (API) material alone.

[0049] The composite active particles may also contain active pharmaceutical ingredient (API) material in crystalline form. Thus, there may be a mixture of amorphous API and crystalline API. Typically, at least 50% or more, or at least 70% or more, or at least 90% or more, or at least 95% or more of the total API is in amorphous form. In one aspect, 99% or more, or 100% of the API is in amorphous form.

[0050] The excipients present in the composite particles may be in an amorphous form, or may be in a crystalline form. One or more excipient components may be in a crystalline form, while one or more excipient components may be in an amorphous form. For example, an amino acid component (e.g., leucine) may be in a crystalline form. And a sugar component (e.g., trehalose) may be amorphous. Typically, when an amorphous form is employed, at least 50% or more, or at least 70% or more, or at least 90% or more, or at least 95% or more of the excipients will be in an amorphous form. In one aspect, 99% or more, or 100% of the excipients are in an amorphous form. Spray drying processes may be used to obtain APIs and excipients in amorphous or substantially amorphous form. A preferred aspect includes leucine in a crystalline form and trehalose in an amorphous form.

[0051] In one aspect of the present disclosure, the composite active granules comprise about 10% to about 90% active pharmaceutical ingredient (API) material by weight of the composite active granules. More preferably, the composite active granules comprise 50% to 80% API.

[0052] In other aspects, in the pharmaceutical composition of the present invention, the excipient includes an amino acid, or a sugar, or a mixture of an amino acid and a sugar. One or more amino acids can be used. One or more sugars can be used.

[0053] The amino acid component may for example comprise leucine, tryptophan, alanine, valine, isoleucine, trileucine, dileucine, methionine, phenylalanine or proline or a mixture of two or more thereof. Preferably, the amino acid component comprises leucine, isoleucine, trileucine or dileucine or a mixture of two or more thereof. Leucine is generally preferred. Enantiomers may be used, for example L-leucine or D-leucine.

[0054] The sugar component can comprise any suitable sugar. Examples are monosaccharides and disaccharides. In some aspects, preferably, the sugar comprises a disaccharide. For example, the sugar can comprise trehalose, lactose, mannitol or sucrose or a mixture of two or more thereof.

[0055] In a preferred aspect, the sugar preferably comprises trehalose, lactose, or sucrose or a mixture of two or more thereof. Trehalose is generally preferred.

[0056] A combination of leucine (which may be, for example, leucine, isoleucine, trileucine or dileucine, L-leucine or D-leucine) and trehalose is a preferred excipient. Trehalose or its derivatives may also be used alone as an excipient.

[0057] In other aspects of the disclosure, the spray-dried cohesive composite active particles comprise about 10 to about 85% by weight of the pharmaceutical composition. In a more preferred embodiment, the spray-dried composite active particles comprise about 50 to about 85% by weight of the pharmaceutical composition.

[0058] The carrier particles (which are discrete particle groups and separated from the spray-dried cohesive composite active particles) can be selected, for example, from the group comprising lactose, mannitol, trehalose, raffinose, sucrose, microcrystalline cellulose, or a mixture of two or more thereof. In a preferred aspect, the carrier particles preferably comprise lactose, and more preferably comprise lactose monohydrate, or a mixture of lactose and lactose monohydrate.

[0059] In one aspect, the carrier particles comprise from about 15% to about 90% by weight of the pharmaceutical composition. In a more preferred embodiment, the carrier particles comprise from about 15% to about 50% by weight of the pharmaceutical composition.

[0060] In a preferred aspect, the mass median aerodynamic diameter (MMAD) of the carrier particles is greater than the mass median aerodynamic diameter (MMAD) of the spray-dried cohesive composite active particles. Preferably, the MMAD of the carrier particles is greater than 10 μm, more preferably greater than 25 μm, or greater than 50 μm. It has been found that an MMAD in the range of about 50 μm to about 100 μm can produce good results. For example, a range of about 50 μm to about 75 μm can be used. We have found advantages from the MMAD of the carrier particles being significantly greater than the MMAD of the spray-dried cohesive composite active particles.

[0061] In other aspects of the present invention, there is provided a method for preparing the pharmaceutical composition described herein, the method comprising the following steps:

[0062] i) providing a solution of an active pharmaceutical ingredient (API) material and a solution of an excipient, which may be a separate solution or a combined solution, and spray drying to provide cohesive composite active particles, wherein each composite active particle comprises an active pharmaceutical ingredient (API) material and an excipient;

[0063] ii) mixing the spray-dried cohesive composite active particles with carrier particles to form a physical mixture.

[0064] As stated above, the spray-dried cohesive composite active particles and the carrier particles are two separate, discrete particle populations.

[0065] In the presently disclosed process, after step (i) or after step (ii), or after both, a post-drying or conditioning step may be performed.

[0066] In other aspects of the method, the size distribution of the composite active particles can be controlled to obtain a desired distribution. For example, the composite active particle size distribution can be controlled to a Dv50 value equal to or < 5 μm.

[0067] Thus, in an additional aspect, the present invention provides spray-dried cohesive composite active particles having a Dv50 value of about 1 to about 3 μm.

[0068] In step (ii) of the process, mixing may comprise high shear or low shear mixing methods. Typically low shear mixing is used and we have found that this produces good results.

[0069] In other aspects, the invention provides a blister or a series of blisters, or one or more capsules for a dry powder inhaler (DPI), comprising the pharmaceutical composition of the invention described herein. It should be understood that this can be achieved by methods known in the art, wherein the pharmaceutical composition is filled into a blister or capsule; or in a device such as a reservoir type dry powder inhaler.

[0070] Thus, there is also provided a dry powder inhaler (DPI) comprising a blister or a series of blisters, or one or more capsules, comprising a pharmaceutical composition of the invention as described herein.

[0071] The present invention also provides a dry powder inhaler (DPI) that relies on turbulence from an airflow to move dry powder, such as a reservoir device comprising a pharmaceutical composition of the present invention as described herein. It should be understood that several inhaler devices (primary examples being DPI reservoir devices) rely on turbulence from an airflow to move dry powder. Therefore, the pharmaceutical composition described herein can be used with such devices, such as medium to high resistance drug DPI devices, such as DPI reservoir devices, alternatively only referred to as reservoir devices; or capsule-based devices and achieve particularly good results.

[0072] The present invention also provides a pharmaceutical composition according to the invention described herein for use as a medicament. It should be understood that the API component of the composition can be used to treat a variety of medical conditions. Administration to a patient is preferably via a dry powder inhaler, as described herein.

[0073] The present invention is particularly useful in treating respiratory conditions or disorders. Accordingly, the present invention also provides a pharmaceutical composition of the invention described herein for use in treating a pulmonary condition.

[0074] According to the present invention, an inhalable pharmaceutical composition is provided, which comprises spray-dried cohesive active particles and carrier particles, both of which are mixed by physical means. In addition, the solubility of the active substance of the composite particles is higher than that of its crystalline micronized form. This formulation strategy presents several advantages in the field of inhalation. On the one hand, compared with crystalline micronized materials, the formulation presents increased administration efficiency by increasing solubility and improving aerosolization. Using high resistance equipment (such as DPI reservoir equipment), aerosolization (i.e., fine particle dosage) is even higher than the composite particles spray-dried separately. On the other hand, compared with the composite particles alone, the mixture presents physical properties, such as fluidity and cohesiveness, which promote a smoother capsule filling manufacturing process. The above properties lead to more streamlined scale and industrialization. The present invention can be applied to low-solubility compounds, which promote higher bioavailability due to higher administration efficiency. In addition, the present invention can be applied to unstable compounds that cannot tolerate grinding technology well.

[0075] The spray-dried composite particles provided by the present invention are significantly different from the prior art in at least two main features. On the one hand, they can be amorphous (active ingredient and at least one excipient), which leads to an increase in the dissolution rate of the active ingredient, thereby leading to a lower dosage and a better therapeutic effect. This allows a higher drug load to be applied to the lungs, which is mandatory for the case of drug compounds for acute treatment, such as, but not limited to, antibiotics, antivirals, vaccines, proteins and peptides. On the other hand, the spray-dried composite particles of the present invention contain excipients as the intrinsic part of primary particles, which is ideal for preparing an inhalable formulation with improved and repeatable physical and chemical properties. Even, the composite particles are particularly useful for particle engineering of unstable active ingredients, which cannot be ground by conventional techniques due to their physical and / or chemical degradation. As far as is known, the composite particles in the prior art themselves are related to an increase in drug delivery, but this is not observed in reservoirs and blister devices, where the dispersion mechanism is not effective enough or the intensity is not enough to depolymerize the spray-dried composite particles of this bonding. In this case, compared with independent composite particles, the present invention presents obvious advantages. The formulations provided by the present invention demonstrate improved aerodynamic performance compared to the spray-dried composite particles alone.

[0076] The present invention is not a common carrier-based formulation in which a crystalline API is mixed with fine and coarse lactose. The purpose of the present invention is to combine two independent formulation technologies, which the prior art shows should not be combined. The composite particles described in the prior art arose from the need to solve problems that carrier-based formulations could not solve. Combining these technologies is not a simple approach and previous disclosures have not disclosed doing so. In addition, all previously described composite formulations claim to be carrier-free, which was considered the greatest advantage of composite particles in the prior art. In contrast, the present invention has shown that this is not true for all formulation and equipment combinations, and there are situations where the combination of spray-dried composite particles plus carrier particles is beneficial.

[0077] Methods for preparing the spray-dried composite particles of the present invention are well known and described in the literature. The preparation of spray-dried particles involves dissolving the active ingredient and excipient in a suitable solvent or solvent mixture. Any suitable concentration of active ingredient and excipient or excipient mixture can be used until the solubility limit. The particles of active ingredient and excipient are obtained by evaporating the solvent by spray drying or other suitable techniques (such as freeze drying), which can be carried out using any suitable or commercially available device. Depending on the selected device, a variety of spray methods can be used, such as two-fluid or three-fluid nozzles, pressure or ultrasonic nozzles. The preferred spray airflow in liters per hour can be adjusted according to the device used, and any suitable spray airflow can be used. Typically, for small-scale units, 150 to 300 milliliters per hour are preferred. On an industrial scale, different flow rates can be used. Any suitable drying temperature can be used, ranging from about 30°C to about 220°C. The inlet temperature can be adjusted to achieve the desired outlet temperature. Any suitable solution flow rate can be used. Parameters such as outlet temperature, spray flow rate, solution concentration, solution flow rate, etc. can be combined and adjusted to obtain a compound with a suitable quality. The spray-dried composite active particles obtained are amorphous and stable over time. The particle formation process in the spray dryer is controlled to obtain the desired particle size. This type of drying technology is usually defined by a medium particle size distribution ranging from below 25 μm and above 1 μm, producing a powder with a low density (usually around 0.1 g / m 3 and 0.5g / m 3 between), and high adhesion.

[0078] In a preferred embodiment, the spray-dried composite active particles have a particle size suitable for inhalation, i.e., a mass median aerodynamic diameter of less than 10 μm, more preferably less than 5 μm. In another embodiment, the spray-dried composite active particles are amorphous and have a higher dissolution rate than the active ingredient crystalline isolated form. In a preferred embodiment, the composite active particles include, but are not limited to, active pharmaceutical ingredients (APIs) from the following therapeutic groups: antibiotics, antifungal agents, antiviral agents, antipsychotic agents, immunosuppressants, bronchodilators, anti-Parkinson's disease agents, anti-inflammatory drugs or anticancer drugs. Examples of active ingredients useful in the present invention include, but are not limited to, streptomycin, isoniazid, para-aminosalicylic acid, tobramycin, gentamicin, rifampicin, pyrazinamide, ethambutol, colistin, aztreonam, ciprofloxacin, amoxicillin, fluoroquinolone, cefuroxime, cefpodoxime, itraconazole, voriconazole, pentamidine, bevacizumab, paclitaxel, ceritinib, tacrolimus, fluticasone, salmeterol, salbutamol, beclomethasone, levodopa, loxapine, remdesivir, amantadine, ribavirin, zanamivir, rimantadine, oseltamivir, acyclovir, foscarnet, peramivir, baloxavirmarboxil, ipratropium bromide, aclidinium bromide, tiotropium bromide, revefenacin, pirfenidone or nintedanib.

[0079] In a preferred aspect, the API is an antibiotic or antiviral compound. For example, the API can be a broad-spectrum antiviral compound, such as remdesivir. The antiviral compound can be a protide compound (a prodrug of a nucleotide), which can diffuse into cells.

[0080] In another preferred aspect, API can be an antibiotic, such as ansamycin antibiotic. Ansamycin is a family of bacterial secondary metabolites, which show antimicrobial activity to many gram-positive bacteria and some gram-negative bacteria, and includes a variety of compounds, including varicose streptococcin and rifamycin. Ansamycin antibiotic compounds can have an aromatic moiety, which can be a naphthalene ring or a naphthoquinone ring (such as in rifamycin and naphthomycins), or another variant is composed of a benzene or benzoquinone ring system (such as in geldanamycin or ansamitocin). Rifampicin is a preferred compound.

[0081] In one aspect, the API may exclude methacholine, or histamine, or nicotine, or salts thereof.

[0082] In one aspect, the composition of the present invention may exclude anticholinergic compounds as API. Specifically, the composition may exclude compounds as shown below as API, wherein X - Represents negatively charged anions:

[0083]

[0084] In one aspect, the compositions of the invention may exclude organic, physiologically acceptable, sterically demanding acids as part of the spray-dried composite particles; and / or as part of a separate carrier particle component. Such acids (which may be excluded) may be selected from ascorbic acid, fruit acids or food acids and monovalent, divalent or trivalent carboxylic acids.

[0085] In a preferred embodiment, the spray-dried composite active particles comprise amino acids, sugars or mixtures thereof. In a more preferred embodiment, the amino acids comprise leucine, tryptophan, alanine, valine, isoleucine, trileucine, dileucine, methionine, phenylalanine, proline or mixtures thereof. In a more preferred embodiment, the sugar comprises trehalose, lactose, mannitol, sucrose or mixtures thereof.

[0086] The formulation of the present invention is composed of spray-dried composite active particles (accounting for 10 to 85% of the total formulation weight) and carrier particles (accounting for 15 to 90% of the total formulation weight), and the two are physically mixed. In a preferred embodiment, the carrier particles are selected from the group consisting of, but not limited to, lactose, mannitol, trehalose, raffinose, sucrose, or microcrystalline cellulose or a mixture thereof.

[0087] The formulation of the present invention is produced by mixing the spray-dried composite particles with a carrier. This is generally a physical mixing step, and any suitable mixing technique can be used. In a more preferred embodiment, the mixing step can be performed by high shear mixing or low shear mixing. The carrier particles preferably contain lactose, mannitol, trehalose, raffinose, sucrose or microcrystalline cellulose or a mixture thereof.

[0088] The formulation of the present invention may be filled into a device or capsule. More preferably, the formulation of the present invention may be filled into a reservoir or blister-based device.

[0089] The formulation method of the present invention brings a new area of ​​interest by combining two opposing formulation technologies to improve drug delivery, especially delivery in high resistance drug devices.

[0090] In summary, the method for producing the preparation of the present invention generally includes the following three steps:

[0091] a. Spray-dried composite particle manufacturing;

[0092] b. mixing the spray-dried composite particles with carrier particles;

[0093] c. Optionally, fill the final mixture into suitable containers (blister cavities, capsules or reservoirs).

[0094] Certain specific aspects and embodiments of the present invention will be described in more detail with reference to the following examples. The examples are given to aid in the understanding of the present invention but are not intended to and should not be considered to limit the scope thereof in any way. The experiments reported were performed using a BUCHI B-290 Advanced Spray Dryer.

[0095] Embodiment 1:

[0096] The formulations are prepared according to the present invention. To prepare the spray-dried particles, the active ingredient is dissolved and the excipient is dissolved in a suitable solvent. A laboratory-scale spray dryer (Büchi, Model B-290) equipped with a three-fluid nozzle is used to spray and dry the solution. Co-current nitrogen is used to promote drying after spraying. The spray drying unit is operated in an open cycle mode (i.e., without recirculation of drying gas). Figure 1 The spray drying apparatus used is shown schematically.

[0097] Before the solution is fed into the nozzle, the spray drying unit is stabilized with nitrogen to ensure stable inlet (T_in) and outlet temperatures (T_out). After stabilization, the solution is fed into the nozzle by a peristaltic pump and atomized at the nozzle tip. The droplets are then dried in the spray drying chamber by current nitrogen. The air stream containing the dried particles is directed into a cyclone separator and collected at the bottom. The main operating parameters during the spray drying process are summarized in Table 1.

[0098] Table 1 – Summary of major operations

[0099]

[0100] The compound obtained using the process of the present invention is an amorphous solid having a higher dissolution rate than the corresponding crystalline form. Several tests confirm its amorphous form, such as x-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC).

[0101] The appearance of the atomized material was characterized using a scanning electron microscope (SEM). Figure 2 Representative images of the obtained particles are shown.

[0102] The X-ray powder diffraction pattern of the spray-dried composite particles obtained according to the method described herein is presented in Figure 3 In the figure, the peak is overlaid with L-leucine crystalline particles to confirm that the peak is from L-leucine, while the active ingredient is in amorphous form. Figure 4 Differential scanning calorimetry (DSC) of the obtained spray-dried composite particles is presented.

[0103] As measured by the Franz cell apparatus, the composite active particles demonstrated higher solubility compared to the crystalline micronized particles (obtained by jet milling), see, for example, Figure 5. The dissolution profiles of jet-milled and spray-dried remdesivir formulations were determined using a Franz cell diffusion apparatus previously described in the literature. In brief, 2 mg of powder was weighed onto the filter and clamped onto each cell of a multi-station Franz cell (VB6, PermeGear Inc.). Each cell was contained within a heated water jacket, which was preheated and then maintained at 37 ± 0.05 ° C by a circulating water bath throughout the experiment. At the start of the experiment, 23 mL of HBSS solution was placed in the water bath in each cell and pumped into the inlet of the Franz cell at 5 mL / min by a multichannel peristaltic pump. The sampling port of the cell is connected to a second pump channel, which returns the sample flow to the 23 mL water tank. The constant stirring of the dissolution medium and the renewal through the pumping port ensure a constant volume within the Franz cell, thereby ensuring that the filter is uniformly wetted and the water tank conditions remain constant during the experiment. At predetermined time intervals (up to 24 h), 0.6 mL samples were withdrawn from the reservoir and analyzed in triplicate by HPLC.

[0104] The obtained composite active granules were mixed with crude lactose and the formulation composition is shown in Table 2. The spray-dried composite granules and crude lactose were mixed in a low shear mixer in two steps. The first step involved mixing 66% w / w of total lactose with 50% w / w of the total amount of composite active granules at 96 rpm for 5 minutes. The second step involved adding the remaining lactose and composite active granules and mixing for another 5 minutes at 96 rpm.

[0105] Table 2 – Composition of the formulations

[0106]

[0107] The obtained mixture was filled into a reservoir-type device. The filling weight used was 31 mg. The filling was carried out in an auger filling principle device, and no clogging was observed. The filling time for each cavity was less than 40 seconds, which is much lower than that of the spray-dried composite particles alone. The aerodynamic performance of the spray-dried composite particles (A), composite mixture (B) (i.e., spray-dried composite particles plus lactose) and carrier-based mixture (C) (i.e., only lactose plus micronized REM) was evaluated by the next generation impactor (NGI). The results are presented in Table 3. Compared to the emission dose of 7.9 mg of the composite mixture, the emission dose (ED) of the composite active particles alone was 2.5 mg. In the case of the composite active particles alone, most of the powder remained in the device (6.5 mg), while in the case of the composite mixture, only a few micrograms of powder remained in the device (0.8 mg). This shows that for the composite particles alone, the circulation through the reservoir device is not enough to fluidize the powder and make it flow out. In vivo, the situation may be even worse, especially when the respiratory flow rate is impaired. The fine particle dose (FPD) of the composite mixture is much higher than that of the composite active particles alone, 3.9 mg and 0.3 mg respectively. This indicates that not only is the emitted dose higher, but also the dose that reaches the lungs and will have a therapeutic effect is higher. This fine particle dose is even higher than that of the common carrier-based mixture with micronized active ingredients (i.e., carrier-based mixture, C).

[0108] Table 3 – Aerodynamic performance measured by NGI

[0109]

[0110]

[0111] The results shown demonstrate that the formulation of the present invention (composite mixture) is more efficient in dosing, also having a higher dissolution rate and a higher fine particle dose than the equivalent crystalline form. The formulation of the present invention also has a higher emission dose and fine particle dose when compared to the spray-dried composite particles alone. In addition, the formulation of the present invention substantially solves the processability problems associated with the high cohesiveness of the spray-dried composite active particles seen during the filling process.

[0112] Embodiment 2:

[0113] The formulations are prepared according to the present invention. To prepare the spray-dried particles, the active ingredient is dissolved and the excipient is dissolved in a suitable solvent. A laboratory-scale spray dryer (Büchi, Model B-290) equipped with a two-fluid nozzle is used to atomize and dry the solution. Co-current nitrogen is used to promote drying after atomization. The spray drying unit is operated in an open cycle mode (i.e., without recirculation of drying gas). Figure 1The spray drying apparatus used is shown schematically.

[0114] Before the solution is fed into the nozzle, the spray drying unit is stabilized with nitrogen to ensure stable inlet (T_in) and outlet temperatures (T_out). After stabilization, the solution is fed into the nozzle by a peristaltic pump and atomized at the nozzle tip. The droplets are then dried in the spray drying chamber by the current nitrogen. The airflow containing the dried particles is directed into a cyclone separator and collected at the bottom. The main operating parameters during the spray drying process are summarized in Table 4.

[0115] Table 4 – Summary of major operating conditions

[0116]

[0117] The compound obtained using the method of the present invention is an amorphous solid having a higher dissolution rate than the corresponding crystalline form. Its amorphous form can be confirmed by x-ray powder diffraction (XRPD). Figure 6 Presented are X-ray powder diffraction patterns of spray-dried composite particles obtained according to the methods described herein.

[0118] The obtained composite active granules were mixed with crude lactose and the formulation composition is shown in Table 5. The spray-dried composite granules and crude lactose were mixed in a low shear mixer in two steps. The first step involved mixing 66% w / w of total lactose with 50% w / w of the total amount of composite active granules at 96 rpm for 5 minutes. The second step involved adding the remaining lactose and composite active granules and mixing at 96 rpm for another 5 minutes.

[0119] Table 5 – Formulation composition

[0120]

[0121] The obtained mixture is filled into a reservoir-type device. The filling weight used for the composite particles is 20 mg, and the filling weight used for the carrier-based formulation is 30 mg to maintain the nominal dose. The filling is carried out in an auger filling principle device, and no clogging is observed. The aerodynamic performance of the spray-dried composite particles (A) and the composite mixture (B) (i.e., spray-dried composite particles plus lactose) was evaluated by the next generation impactor (NGI). The results are presented in Table 6. Although the emission dose (ED) is similar, the fine particle fraction (FPF) of the composite mixture (B) is higher. The fine particle dose (FPD) of the composite active particles alone is 1.5 mg, compared to the FPD of the composite mixture of 2.6 mg. The fine particle dose (FPD) of the composite mixture is higher than the fine particle dose of the composite active particles alone. This indicates that the dose that reaches the lungs and will have a therapeutic effect is higher.

[0122] Table 6 – Aerodynamic performance measured by NGI

[0123]

[0124]

[0125] *Dosage based on powder determination DSC method:

[0126] Number of sample trays 23 Sample quality 5.149mg Disk quality 0.000mg Reference disk quantity 54 Reference sample quality 0.000mg Reference disc quality 53.910mg Disk Type Tzero Aluminum

[0127]

[0128]

Claims

1. An inhalable pharmaceutical composition comprising: (i) spray-dried cohesive composite active particles, each composite active particle comprising an active pharmaceutical ingredient (API) material and an excipient; and (ii) Carrier particles The composite active particles are mixed with the carrier particles in the form of a physical mixture.

2. The pharmaceutical composition according to claim 1, wherein the composite active particles have a mass median aerodynamic diameter (MMAD) equal to or less than 10 μm.

3. The pharmaceutical composition according to claim 2, wherein the composite active particles have a mass median aerodynamic diameter (MMAD) equal to or less than 5 μm.

4. A pharmaceutical composition according to any one of the preceding claims, wherein the active pharmaceutical ingredient (API) material has a solubility and a dissolution rate that is higher than that of a crystalline isolated form of the API.

5. A pharmaceutical composition according to any one of the preceding claims, wherein the composite active particles comprise an active pharmaceutical ingredient (API) material in an amorphous form.

6. A pharmaceutical composition according to any one of the preceding claims, wherein the composite active particles are more soluble than the active pharmaceutical ingredient (API) material particles alone.

7. A pharmaceutical composition according to any one of the preceding claims, wherein the composite active particles further comprise an active pharmaceutical ingredient (API) material in crystalline form.

8. A pharmaceutical composition according to any one of the preceding claims, wherein the composite active particle comprises from 10% to 90% active pharmaceutical ingredient (API) material by weight of the composite active particle.

9. A pharmaceutical composition according to any one of the preceding claims, wherein the excipient comprises an amino acid, or a sugar, or a mixture of an amino acid and a sugar.

10. The pharmaceutical composition according to claim 9, wherein the amino acid comprises leucine, tryptophan, alanine, valine, isoleucine, trileucine, dileucine, methionine, phenylalanine or proline, or a mixture of two or more thereof.

11. The pharmaceutical composition according to claim 9 or 10, wherein the amino acid comprises leucine, isoleucine, trileucine or dileucine or a mixture of two or more thereof.

12. A pharmaceutical composition according to any one of claims 9 to 11, wherein the sugar comprises a disaccharide.

13. The pharmaceutical composition according to any one of claims 9 to 12, wherein the sugar comprises trehalose, lactose, mannitol or sucrose or a mixture of two or more thereof.

14. The pharmaceutical composition according to any one of claims 9 to 13, wherein the sugar comprises trehalose, lactose or sucrose or a mixture of two or more thereof.

15. A pharmaceutical composition according to any one of the preceding claims, wherein the composite active particles comprise from about 10% to 85% by weight of the pharmaceutical composition.

16. A pharmaceutical composition according to any one of the preceding claims, wherein the composite active particles comprise about 50% to 85% by weight of the pharmaceutical composition.

17. A pharmaceutical composition according to any one of the preceding claims, wherein the carrier particles are selected from the group comprising lactose, mannitol, trehalose, raffinose, sucrose, microcrystalline cellulose or a mixture of two or more thereof.

18. The pharmaceutical composition according to claim 17, wherein the carrier particles comprise lactose or lactose monohydrate, or a mixture of lactose and lactose monohydrate.

19. A pharmaceutical composition according to any preceding claim, wherein the carrier particles comprise about 15% to 90% by weight of the pharmaceutical composition.

20. A pharmaceutical composition according to any preceding claim, wherein the carrier particles comprise about 15% to 50% by weight of the pharmaceutical composition.

21. A pharmaceutical composition according to any one of the preceding claims, wherein the carrier particles have a mass median aerodynamic diameter (MMAD) greater than 25 μm.

22. A pharmaceutical composition according to any one of the preceding claims, wherein the carrier particles have a mass median aerodynamic diameter (MMAD) of 50 to 100 μm.

23. A process for preparing a pharmaceutical composition according to any one of the preceding claims, comprising the steps of: i) providing a solution of an active pharmaceutical ingredient (API) material and a solution of an excipient, which may be a separate solution or a combined solution, and spray drying to provide cohesive composite active particles, wherein each composite active particle comprises an active pharmaceutical ingredient (API) material and an excipient; ii) mixing the spray-dried cohesive composite active particles with carrier particles to form a physical mixture.

24. A method for preparing a pharmaceutical composition according to claim 23, wherein after step (i) or after step (ii), or after step (i) and after step (ii), a post-drying or conditioning step is performed.

25. A method for preparing a pharmaceutical composition according to claim 23 or 24, wherein the composite active particle size distribution is controlled to a Dv50 equal to or < 5 μm.

26. A process for preparing a pharmaceutical composition according to any one of claims 23 to 25, wherein the mixing in step (ii) comprises a high shear or low shear process.

27. A blister or a series of blisters, or one or more capsules, for use in a dry powder inhaler, comprising a pharmaceutical composition according to any one of claims 1 to 22.

28. A dry powder inhaler comprising a blister or a series of blisters according to claim 27, or one or more capsules.

29. A dry powder inhaler which is a reservoir device comprising a pharmaceutical composition according to any one of claims 1 to 22.

30. A pharmaceutical composition according to any one of claims 1 to 22 for use as a medicament.

31. A pharmaceutical composition according to claim 30 for use in the treatment of a pulmonary condition.

Images