Combination of inhalation complex and carrier-based formulations

Abstract

The inhalable pharmaceutical composition comprises (i) spray-dried agglomerated conjugate active particles, each conjugate active particle comprising an active pharmaceutical ingredient (API) material and an excipient, and (ii) carrier particles, the conjugate active particles and carrier particles being blended as a physical mixture. A method of preparing the pharmaceutical composition comprises: i) providing a solution of an active pharmaceutical ingredient (API) material and a solution of an excipient, which may be separate or combined solutions, and spray drying to provide agglomerated conjugate active particles, each conjugate active particle comprising an active pharmaceutical ingredient (API) material and an excipient, and ii) blending the spray-dried agglomerated conjugate active particles with carrier particles to form a physical mixture. The composition may be used in a dry powder inhaler (DPI), particularly a reservoir-type DPI device.

Description

Detailed Description of the Invention

[0001] The present invention relates to an inhalable pharmaceutical formulation that enhances dosing efficiency by either increasing the solubility of the active ingredient and / or increasing the aerodynamic performance of the spray-dried particles. More specifically, the present invention relates to a method for producing said formulation by a combination of unit operations of spray drying and blending. Furthermore, 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 for inhalable powders with high drug load or insoluble active ingredients.

[0002] [Background of the invention] The present invention relates to an inhalable pharmaceutical formulation that enhances dosing efficiency by either increasing the solubility of the active ingredient and / or increasing the aerodynamic performance of the spray-dried particles. More specifically, the present invention relates to a method for the manufacture of said formulation by a combination of unit operations of spray drying and blending. Furthermore, 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 for inhalable powders with high drug load or insoluble active ingredients.

[0003] Carrier-based formulations and composite particles for inhalation are both widespread solutions for the delivery of active ingredients to the lungs in the form of a powder. Powder-based inhalers are often used for the treatment of chronic respiratory diseases such as asthma or chronic obstructive pulmonary disease. Nevertheless, in the past few years, dry powder formulations have deserved considerable attention for acute respiratory treatments such as infectious diseases or vaccines. Dry powder formulations have led to an increased interest in the delivery to patients of high loadings of pharmaceutical compounds such as antibiotics, antivirals, vaccines, proteins, peptides and other drugs capable of acting systemically, administered through the lungs. Such compositions with high drug loadings are typically less than 0.1 g / cm, especially for composite engineered particles. 3 ~0.5g / cm 3These powders are typically characterized by high adhesiveness and cohesion resulting from low median particle size combined with low bulk density in the range of 0.1 to 0.5 μm.

[0004] The inventors therefore recognize that, taking into account the characteristics of the powders, it is a great challenge to load these powders into devices for inhalation delivery. These powders are frequently associated with long loading process times, high variability between doses and increased challenges in the selection of loading principles. These challenges lead to time-consuming operations on an industrial scale and loss of efficiency and reproducibility.

[0005] Moreover, the inventors have recognized that efficiently aerosolizing powders and minimizing retention on the device, especially in medium to high resistance devices such as reservoir-type DPI devices, is also a challenge.

[0006] The following discussion of the prior art is intended to place the invention in the proper technical context and enable an appreciation of the importance of the invention.

[0007] Pulmonary drug delivery through dry powder inhalers (DPIs) presents several advantages due to their propellant-free characteristics, high patient compliance, high dose loading and drug stability. This has led to rapid development in recent years to realize the full potential of the lung for local and systemic treatment of diseases. Nevertheless, DPIs are inherently complex and their performance depends on many aspects including the inhaler design, the powder formulation and the airflow generated by the patient.

[0008] Aerosol particles inhaled from a DPI exhibit different diameters, leading to regional lung deposition differences and resulting in variable therapeutic efficacy. The fine particle component in an aerosol is the therapeutic fraction, defined as the percentage of particles with an aerodynamic diameter smaller than 5 μm, or for certain particle size measuring devices, the cutoff diameter close to 5 μm. Thus, the degree of dispersibility is an important consideration for both the quality and efficacy of a pharmaceutical aerosol. The fine particle dose (FPD) is the mass in milligrams of particles with a cutoff diameter smaller than 5 μm. The fine particle fraction (FPF) is the fine particle dose divided by the total emitted volume.

[0009] The highly cohesive nature of micronized active materials prevents accurate metering of the low doses required for inhalation drug products and makes them difficult to handle during the material preparation process. To overcome the handling and dosing problems of DPI formulations and optimize the fluidization properties, micronized APIs are typically blended with coarse materials that can be easily aerated and fluidized. For carrier-based DPI formulations, the materials are usually coarse-sized sugar fractions, such as lactose monohydrate. In the carrier-based field, there are several examples where micronized active ingredients are blended with sugars, namely lactose.

[0010] Carrier-Based Formulations US Patent Publication No. 2017 / 0266122 describes a pharmaceutical composition comprising active particles of a complex of an active material and magnesium stearate and carrier particles for pulmonary delivery. EP Patent Publication No. 1913939 describes a method for making particles composed of an active ingredient and an excipient, comprising a co-grinding step and blending the co-grinded particles with a carrier. EP Patent No. 1617820 describes a dry powder inhaler comprising a formulation having an active ingredient co-milled with an excipient that is further bound to a carrier (jet-milled complex particles). These are typical carrier-based formulations with milled active ingredients combined with excipients by dry coating and / or dry milling. The excipients are used to reduce cohesion between the milled particles. These disclosures are significantly different from the present invention, since the complex particles described in EP Patent No. 1617820 have substantially different characteristics when compared to the present invention, taking into account the considerable differences in the method of making the complex particles. The preparation method for producing composite particles disclosed in these publications is jet milling, which means dry milling. In contrast, the preparation method proposed in the present invention is spray drying, which does not include a milling step, which brings several advantages in terms of particle engineering. Furthermore, the milled particles in publications US2017 / 0266122, EP1913939 and EP1617820 are crystalline particles, 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 characteristics that show several advantages when compared to milled active materials.

[0011] 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 concerned with the different preparation methods for composite active particles when compared to the present invention. This publication uses a common milling step, which is in contrast to the preparation method of the proposed invention (spray drying), and the large difference between the methods results in significantly different final composite particles as previously mentioned.

[0012] EP 2821061 describes a dry powder formulation comprising a micronized active agent and a carrier agent, where fine and coarse particles of the carrier agent are employed. This approach is well known in the pharmaceutical industry for dry powder inhalers, as it allows a significant increase in the fine particle delivery of the active material. Nevertheless, this publication differs significantly from the present invention, considering that these improvements are appropriate for low dose milled particles, representing as an example 0.05-4.5% w / w active ingredient. It is common knowledge in the field of respiratory formulations that for carrier-based formulations, increasing the concentration of active ingredient in the blend results in an increase in the number and size of individual agglomerates, as well as multiple layers of densely packed active ingredient on the surface of the lactose carrier. The active ingredient present in the multiple layers disperses as dense agglomerates rather than individual primary particles, which results in a decrease in aerosol performance and a decrease in the fraction deposited in the lungs (fine particle fraction).

[0013] Thus, the inventors have recognized that carrier-based formulations exhibit drawbacks, especially for high drug loadings (greater than 10% w / w active material).Several studies have demonstrated that as the active material concentration in the blend increases, the aerosol performance of the formulation decreases inversely proportionally.

[0014] spray dried composite particles The majority of commercially available DPIs rely on the use of a physical mixture of a coarse carrier (most commonly lactose monohydrate, 50-100 μm in size) with small particles of inhalable drug (1-5 μm) to overcome the strong cohesive and adhesive properties of the drug and to improve metering. This balance must be optimized to successfully deliver the dose to the deep lung. Unfortunately, this balance is difficult to achieve due to the complexity of interparticle forces, which depend on several intrinsic and extrinsic factors. Thus, it has become generally accepted to achieve deep lung deposition of only 30% of the active ingredient dose. A low percentage such as 30%, in addition to the high mass of the coarse carrier used, is a significant barrier to the use of DPIs to deliver high doses of drugs.

[0015] In the last decade, the performance of DPIs has been significantly improved using carrier-free engineered drug particles with modified excipient systems by spray drying (hereafter spray-dried particles). Spray-dried particles can contain only the active ingredient or can contain at least one excipient in addition to the active ingredient (spray-dried composite particles).

[0016] Spray drying began to be explored for inhalation in the 1980s as an alternative method to create fine particles with desirable flow and dispersion properties without the need for the use of coarse carriers.

[0017] Spray drying is a means to change the physicochemical properties of a material to improve and optimize its aerosol performance as well as its dissolution properties. A solid starting material is dissolved in a liquid medium to be reconstituted with well-controlled characteristics at particle level (size, morphology, polymorphic form, 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 an essential role both in optimizing the aerodynamic performance and in stabilizing the physicochemical properties of the particles (spray-dried composite particles).

[0018] Composite particles produced by spray drying are described, for example, in US Patent No. 7,862,834, which describes a spray-dried pharmaceutical formulation comprising particles of an active ingredient and at least one excipient, and a method for making said particles. The particles described herein are composite particles comprising an active ingredient and an excipient that at least partially encapsulates said active ingredient. The particles referred to are significantly different from the present invention, considering that the present manufacturing method typically results in amorphous spray-dried particles, meaning that the active material is molecularly dispersed in at least one excipient, both in an amorphous state. Furthermore, the scope of the present invention is broader than US Patent No. 7,862,834, in that it aims to solve the processability and industrialization problems associated with the low density and high cohesiveness of spray-dried composite particles. Due to the overall small particle size of spray-dried formulations for respiratory administration, handling and processing of these powders is difficult. The large surface area can lead to uncontrolled agglomeration and hinder the filling method. Furthermore, spray dried materials are often not very dense and have poor mechanical stability, so the filling method itself can have a detrimental effect on inhalation success as the powder may be compacted and not redisperse well. The present invention addresses or substantially minimizes these problems.

[0019] The publications WO0062819, KR20010034594A, CA2265198(A1) and EP1925295 describe complex formulations of active ingredients (methacholine, histamine, nicotine or other) and sugar, which are prepared by dissolving or dispersing both ingredients in a suitable solvent to produce a homogeneous solution, and drying the solution by spray drying to form a powder.No additional carrier components are disclosed, which would in fact contradict these teachings.

[0020] In the publication WO2021234366, the composition is provided in the form of an amorphous monoparticulate powder. The particles of the powdered composition described are thus presented as amorphous complexes of the active ingredient, the carrier material and optionally other ingredients. They do not consist of a set of discrete separate particles of different components in the form of a mixture of two or more species, such as a physical association of an ordered or interactive mixture of smaller particles of the active ingredient associated with larger but distinct and chemically distinct particles of the carrier material. The preparation method mentioned in this patent shows that the API and excipients are dissolved in a solvent and the solution is spray-dried, resulting in a molecular mixture of the API and excipients.

[0021] The development of high dose DPIs continues to be hindered by strong and variable interparticle forces that occur between small spray-dried composite particles. Forces such as interparticle forces impede powder flow during processing and dosing, leading to the formation of large intractable agglomerates that can prevent the active ingredient from reaching the lower respiratory tract and cause variable or low fine particle fractions.

[0022] The powder dispersion process in DPI is very complicated and involves several physical mechanisms, namely air turbulence and shear flow induced aerodynamic forces, particle-device sticking in the inhaler body, mechanical vibration and particle-particle collision.The inventors also recognize that another point of improvement is the aerodynamic performance of DPI when dealing with devices that rely solely on the turbulence generated by airflow to aerosolize powder, such as reservoir and blister-based devices.So far, there is no clear or optimized formulation available to improve the aerodynamic performance in such devices.

[0023] None of the aforementioned publications solves all of the problems that the present invention proposes to solve in the context of inhalable products, including in particular increasing the fine particle fraction in reservoirs and / or blister-based devices, increasing solubility (for poorly soluble drugs) and overcoming difficulties related to processability and industrialization.

[0024] [Description of the Invention] The present invention seeks to provide an inhalable pharmaceutical formulation comprising spray-dried cohesive complex particles physically blended with carrier particles. The present invention proposes to enhance dosing efficiency by increasing the solubility of the active ingredient and / or increasing the aerodynamic performance of the spray-dried particles. The increased solubility is achieved through the amorphous state of the spray-dried complex particles. On the other hand, the increased aerodynamic performance is obtained by physically blending the spray-dried complex particles with a carrier. Furthermore, the present invention seeks to provide a method for the manufacture of said formulation by a combination of spray-drying and blending unit operations. Furthermore, the present invention proposes a solution for the processability of highly cohesive powders such as spray-dried powders. Furthermore, the present invention shows a solution for the poor aerosolization of spray-dried complex particles, especially in high resistance devices. The pharmaceutical composition can be applied in the pharmaceutical field, more specifically in inhalable powders with high drug loads or insoluble active ingredients for inhalation.

[0025] In contrast to the disclosures of WO0062819, KR20010034594A, CA2265198(A1) and EP1925295, in the present invention the composite particles (composed of the active ingredient and at least one excipient) provided by spray drying are physically blended with the carrier by low or high shear mixing after the spray drying unit operation. As a result, the final powder properties are substantially different. In the present invention, the complex particles typically have a rather small particle size (Dv90 less than 10 μm) and the carrier particles typically have a larger particle size (Dv90>10 μm), in contrast to the particles described in the publications WO0062819, KR20010034594A, CA2265198(A1) and EP1925295, in which the complex particles of both active ingredients (methacholine, histamine and nicotine) and sugar (carrier) have a Dv90 less than 10 μm. Furthermore, the formulation of the present invention has the advantage that the blend has a sufficient cohesive-adhesive balance between the complex particles and the carrier particles such that the complex particles (containing the active ingredient) are released from the carrier upon actuation. Thus, the carrier remains in the throat and the complex particles flow into the airways. In contrast, the formulations described in WO 0062819, KR20010034594A, CA2265198(A1) and EP 1925295 are only composite particles, so that the active ingredient (methacholine, histamine, nicotine or other) is delivered together with a carrier to the alveoli and lower respiratory tract of the patient.

[0026] In contrast to WO2021234366, in this formulation at least two different types of particles are physically blended, preferably spray-dried complex active particles with a small particle size suitable for inhalation (e.g. dv90≦10 μm) and a carrier with a larger particle size, e.g. dv90≧10 μm. In particular, in this field it is difficult to find a suitable solvent to dissolve both the active ingredient and the excipient, especially when the active ingredient is poorly soluble. In the method of the present invention, the complex particles are made before being blended with a carrier material such as a sugar, which means there is more freedom in the choice of solvent. This is a further advantage of the present invention.

[0027] According to one aspect of the present invention, (i) spray-dried agglomerated composite active particles, each composite active particle comprising an active pharmaceutical ingredient (API) material and an excipient; and (ii) Carrier particles 1. An inhalable pharmaceutical composition comprising: The composite active particles and carrier particles are blended as a physical mixture; Pharmaceutical compositions are provided.

[0028] Further aspects of the invention are described below.

[0029] The term cohesion / agglomeration is well known in the pharmaceutical powder art and generally relates to powder flowability, which is often the most influential property regarding bulk powder behavior. Agglomeration is a mechanism that acts between particles, where one particle has a tendency to "stick" to its particle neighbors.

[0030] The terms "spray dried agglomerated composite active particles" and "composite active particles" are used interchangeably herein.

[0031] The carrier particles are separate and distinct from the composite active particles. Thus, in the present invention, there are two populations of particles. Once each population of particles is obtained, they are mixed or blended into a physical mixture. Thus, they are not manufactured together.

[0032] An inhalable composition is one that is suitable for administration via the inhalation route, i.e., one that can be inhaled through the nasal or oral cavity of a patient in need of the inhalable composition. Preferably, a dry powder inhaler, such as a reservoir device, is employed to administer the composition to the respiratory tract. [Brief description of the drawings]

[0033] [Figure 1] FIG. 2 shows the spray drying design used. [Diagram 2] FIG. 2 shows an SEM image of spray dried composite particles from Example 1. [Diagram 3] FIG. 2 shows the XRPD diffractogram of spray-dried composite particles from Example 1. [Figure 4] FIG. 2 shows a DSC diffractogram of spray-dried composite particles from Example 1. [Diagram 5] 1 is a graph showing the dissolution curves of the spray dried composite particles and the jet milled micronized material from Example 1. [Figure 6] FIG. 2 is a diagram showing the powder X-ray diffraction pattern of the spray-dried composite particles obtained in Example 2.

[0034] The conjugate active particles used in the inhalable pharmaceutical composition of the invention preferably have a mass median aerodynamic diameter (MMAD) of 10 μm or less, more preferably less than 5 μm. The MMAD may for example be in the range 1 to 10 μm, or 1 to 8 μm, or 2 to 6 μm, or 1 to 5 μm.

[0035] In one aspect, the solubility and dissolution rate of an active pharmaceutical ingredient (API) material is higher than that of a crystalline isolated form of the API. The solubility and dissolution rate are typically measured in an aqueous medium or solution. For example, the solubility and dissolution rate can be measured in HBSS (Hank's Balanced Salt Solution). This is useful because it can be adopted to mimic lung fluid.

[0036] In a preferred embodiment, the composite active particles comprise an active pharmaceutical ingredient (API) material in an amorphous form.

[0037] In one aspect, the composite active particles are more soluble than particles of the active pharmaceutical ingredient (API) material alone, especially when the API is in amorphous form.

[0038] The composite active particles may further comprise active pharmaceutical ingredient (API) material in crystalline form. Thus, there may be a mixture of both amorphous 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 embodiment, 99% or more or 100% of the API is in amorphous form.

[0039] The excipients present in the composite particles may be in amorphous or crystalline form. One or more excipient components may be in crystalline form and one or more excipient components may be in amorphous form. For example, an amino acid component such as leucine may be in crystalline form. Meanwhile, a sugar component such as trehalose may be in amorphous form. 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 excipient will be in amorphous form. In one embodiment, 99% or more or 100% of the excipient is in amorphous form. The spray drying method can be used to obtain both the API and the excipient in amorphous or substantially amorphous form. A preferred embodiment includes leucine in crystalline form and trehalose in amorphous form.

[0040] In one embodiment of the present disclosure, the composite active particles comprise from about 10 to about 90% active pharmaceutical ingredient (API) material by weight of the composite active particle. More preferably, the composite active particles comprise from 50 to 80% API.

[0041] In a further embodiment, in the pharmaceutical composition of the present invention, the excipient comprises an amino acid or a sugar or a mixture of an amino acid and a sugar. One or more amino acids may be used. One or more sugars may be used.

[0042] The amino acid component may include, for example, leucine, tryptophan, alanine, valine, isoleucine, trileucine, dileucine, methionine, phenylalanine, or proline, or a mixture of two or more thereof. Preferably, the amino acid component includes leucine, isoleucine, trileucine, or dileucine, or a mixture of two or more thereof. Leucine is often preferred. Enantiomers, such as L-leucine or D-leucine, may be used.

[0043] The sugar component may include any suitable sugar. Examples are monosaccharides and disaccharides. In some embodiments, preferably, the sugar includes a disaccharide. For example, the sugar may include trehalose, lactose, mannitol, or sucrose, or a mixture of two or more thereof.

[0044] In a preferred embodiment, the sugar preferably comprises trehalose, lactose or sucrose or a mixture of two or more thereof, with trehalose being often preferred.

[0045] A combination of a form of leucine (which may be, for example, leucine, isoleucine, trileucine, or dileucine, L-leucine or D-leucine) and trehalose is one preferred excipient. Trehalose or a derivative of trehalose may also be used alone as an excipient.

[0046] In a further aspect of the present disclosure, the spray dried cohesive conjugate active particles comprise from about 10 to about 85% by weight of the pharmaceutical composition. In a more preferred embodiment, the spray dried conjugate active particles comprise from about 50 to about 85% by weight of the pharmaceutical composition.

[0047] The carrier particles, which are a discrete particle population and separate from the spray-dried agglomerated complex active particles, may be selected from the group including, for example, lactose, mannitol, trehalose, raffinose, sucrose, microcrystalline cellulose, or a mixture of two or more thereof. In a preferred embodiment, the carrier particles preferably include lactose and more preferably lactose monohydrate, or a mixture of lactose and lactose monohydrate.

[0048] In one embodiment, the carrier particles comprise about 15% to about 90% by weight of the pharmaceutical composition. In a more preferred embodiment, the carrier particles comprise about 15% to about 50% by weight of the pharmaceutical composition.

[0049] In a preferred embodiment, the mass median aerodynamic diameter (MMAD) of the carrier particles is larger than that of the spray-dried agglomerated composite active particles. Preferably, the MMAD of the carrier particles is larger than 10 μm, more preferably larger than 25 μm or larger than 50 μm. MMADs ranging from about 50 μm to about 100 μm have been found to provide good results. For example, a range of about 50 μm to about 75 μm may be used. The inventors have found advantages resulting from the MMAD of the carrier particles being significantly larger than the MMAD of the spray-dried agglomerated composite active particles.

[0050] In a further aspect of the invention there is provided a method for preparing a pharmaceutical composition as described herein, comprising the steps of: i) providing a solution of an active pharmaceutical ingredient (API) material and a solution of excipients, which may be separate solutions or a combined solution, and spray drying to provide cohesive composite active particles, each composite active particle comprising an active pharmaceutical ingredient (API) material and an excipient; ii) blending the spray dried agglomerated composite active particles with carrier particles to form a physical mixture; A method is provided, comprising:

[0051] As noted above, the spray dried agglomerated composite active particles and the carrier particles are two separate, discrete populations of particles.

[0052] In the method of the present disclosure, a post-drying or conditioning step may be carried out after step (i) or after step (ii), or both.

[0053] In a further aspect of the method, the size distribution of the composite active particles may be controlled to obtain a desired distribution, for example, the size distribution of the composite active particles may be controlled to a Dv50 value of 5 μm or less.

[0054] Thus, in a further aspect, the present invention provides spray-dried cohesive composite active particles having a Dv50 value of from about 1 to about 3 μm.

[0055] In step (ii) of the process, the blending may involve a high shear or low shear blending process. Typically, low shear blending is used and the inventors have found that low shear blending gives good results.

[0056] In a further aspect, the present invention provides a blister or a series of blisters or one or more capsules comprising a pharmaceutical composition according to the present invention as described herein for use in a dry powder inhaler (DPI).As will be appreciated, this can be achieved by methods known in the art where the pharmaceutical composition is loaded into a device such as a blister or capsule or reservoir type dry powder inhaler.

[0057] Thus, there is also provided a dry powder inhaler (DPI) comprising a blister or a series of blisters or one or more capsules containing a pharmaceutical composition according to the invention as described herein.

[0058] The present invention also provides dry powder inhalers (DPIs) that rely on turbulence from an airflow to move dry powder, such as reservoir devices comprising a pharmaceutical composition according to the present invention as described herein. As will be appreciated, some inhaler devices, primarily exemplified by DPI reservoir devices, rely on turbulence from an airflow to move dry powder. Thus, the pharmaceutical compositions described herein can be used with particularly good results with such devices, such as medium to high resistance drug DPI devices, such as DPI reservoir devices, alternatively known simply as reservoir devices, or capsule-based devices.

[0059] The present invention also provides the pharmaceutical composition according to the present invention described herein for use as a medicament.As will be understood, the API components of the composition can be employed to treat various medical conditions.As described herein, administration to a patient is preferably via a dry powder inhaler.

[0060] The present invention is particularly useful for treating respiratory conditions or disorders. Accordingly, the present invention also provides a pharmaceutical composition according to the invention described herein for use in treating a pulmonary condition.

[0061] According to the present invention, an inhalable pharmaceutical composition is provided, comprising spray-dried cohesive active particles and carrier particles, both of which are physically blended. Moreover, the solubility of the active material in the complex particles is higher than that of the crystalline micronized form of the active material. This formulation strategy shows several advantages in the inhalation field. On the one hand, the formulation shows increased dosing efficiency due to increased solubility and improved aerosolization when compared to crystalline micronized materials. Aerosolization, meaning fine particle dose, is even higher when using high resistance devices such as DPI reservoir devices compared to spray-dried complex particles alone. On the other hand, the blend shows physical properties such as flowability and cohesiveness that promote a smoother capsule filling preparation process when compared to the complex particles alone. Said properties lead to a leaner scale-up and industrialization. The present invention can be applied to compounds with low solubility, promoting higher bioavailability as a result of higher dosing efficiency. Furthermore, the present invention can be applied to unstable compounds that do not tolerate milling techniques well.

[0062] The spray-dried composite particles provided by the present invention significantly differ from the prior art in at least two main properties. On the one hand, they can be amorphous (both the active ingredient and at least one excipient), resulting in an increase in the dissolution rate of the active ingredient, resulting in lower doses and higher therapeutic efficacy. This allows the administration of higher drug loads to the lungs, which is essential in the case of pharmaceutical compounds for acute treatments, 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 the excipients as an inherent part of the primary particles, which is ideal for preparing inhalable formulations with improved and reproducible physical and chemical characteristics. Furthermore, said composite particles are particularly useful for particle engineering of unstable active ingredients that cannot be ground by conventional techniques due to their physical and / or chemical degradation. It is now known that the composite particles in the prior art are associated with an increase in drug delivery, which is not observed in reservoir and blister-based devices, where the dispersion mechanisms are not efficient or powerful enough to deagglomerate such cohesive spray-dried composite particles. In this case, the present invention shows a significant advantage when compared to the composite particles alone: ​​the formulations provided by the present invention show better aerodynamic performance compared to the spray-dried composite particles alone.

[0063] The present invention is not a typical carrier-based formulation, but rather a crystalline API blended with fine and coarse lactose. The object of the present invention is the combination of two independent formulation techniques that were not envisaged to be combined in the prior art presented. The complex particles described in the prior art arose from the need to solve problems that carrier-based formulations could not solve. Combining such techniques is not a simple approach, and there is no prior disclosure where this has been done. Furthermore, all previously described complex formulations are claimed to be carrier-free, which is stated in the prior art as the greatest advantage of complex particles. In contrast, the present invention shows that this is not the case for all formulation and device combinations, and that there are cases where the combination of spray-dried complex particles with carrier particles is beneficial.

[0064] 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 the dissolution of the active ingredient and excipients in a suitable solvent or mixture of solvents. Any suitable concentration of active ingredient and excipient or mixture of excipients can be used up to the limit of solubility. The particles of active ingredient and excipients are obtained by evaporation of the solvent by spray drying or other suitable techniques such as freeze drying, carried out using any suitable or commercially available equipment. Depending on the equipment selected, e.g. two or three fluid nozzles, pressure or ultrasonic nozzles, various atomization methods can be used. The preferential atomization gas flow can be adjusted to the equipment used in liters per hour, and any suitable atomization gas flow can be used. Typically, for small scale units, 150 to 300 milliliters per hour is preferred. On an industrial scale, different flows 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. The outlet temperature, atomization flow rate, solution concentration and solution flow rate, among other parameters, can be tailored and adjusted to obtain a compound with suitable quality. The resulting spray-dried composite active particles are amorphous and stable over time. The particle formation process in the spray dryer is controlled to obtain the desired particle size. The range usually defined for this type of drying technology is a moderate particle size distribution below 25 μm and above 1 μm, usually 0.1 g / m 3 and 0.5g / m 3 This results in a powder with low density and high cohesion between 0.01 and 0.1.

[0065] In a preferred embodiment, the spray-dried conjugate active particles have a particle size suitable for inhalation, meaning mass median aerodynamic diameter of less than 10 μm, more preferably less than 5 μm. In another embodiment, the spray-dried conjugate active particles are amorphous and the dissolution rate of the spray-dried conjugate active particles is higher than the crystalline isolated form of the active ingredient. In a preferred embodiment, the conjugate active particles contain an active pharmaceutical ingredient (API) from the following therapeutic groups, including but not limited to: antibiotics, antifungals, antivirals, antipsychotics, immunosuppressants, bronchodilators, antiparkinsonian drugs, anti-inflammatory drugs, or anticancer drugs. Examples of active ingredients that are 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, fluoroquinolones, cefuroxime, cefpodoxime, itraconazole, voriconazole, pentamidine, bevacizumab, paclitaxel, ceritinib, tacrolimus, fluticasone, salmeterol, salbutamol, beclomethasone, levodopa, loxapine, remdesivir, amantadine, ribavirin, zanamivir, rimantadine, oseltamivir, acyclovir, foscarnet, peramivir, baloxavir. Includes marboxil, ipratropium bromide, aclidinium bromide, tiotropium bromide, rebefenacin, pirfenidone or nintedanib.

[0066] In a preferred embodiment, the API is an antibiotic or an antiviral compound.For example, the API can be a broad-spectrum antiviral compound such as Remdesivir.The antiviral compound can be a protide compound (prodrug of nucleotide) that can diffuse into cells.

[0067] In another preferred embodiment, the API can be an antibiotic, such as ansamycin antibiotics. Ansamycins are a family of bacterial secondary metabolites that exhibit antibacterial activity against many gram-positive and some gram-negative bacteria, and include a variety of compounds, including streptovaricins and rifamycins. Ansamycin antibiotic compounds can have an aromatic moiety that can be a naphthalene or naphthoquinone ring, as in rifamycins and naphthomycins, or another variation is a benzene or benzoquinone ring system, as in geldanamycin or ansamitocins. Rifampicin is one preferred compound.

[0068] In one embodiment, the API may exclude methacholine or histamine or nicotine or salts thereof.

[0069] In one embodiment, the compositions of the present invention may exclude anticholinergic compounds as APIs. In particular, the compositions may include compounds as APIs, such as those shown below, where X - indicates a negatively charged anion) may be excluded. [ka]

[0070] In one aspect, the compositions of the present invention may exclude physiologically acceptable and sterically demanding organic acids as part of the spray-dried composite particles and / or as part of another carrier particle component. Such acids, which may be excluded, may be selected from among ascorbic acid, fruit or culinary acids, and mono-, di- or tri-carboxylic acids.

[0071] In a preferred embodiment, the spray-dried conjugate active particles comprise an amino acid, a sugar, or a mixture thereof. In a more preferred embodiment, the amino acid comprises leucine, tryptophan, alanine, valine, isoleucine, trileucine, dileucine, methionine, phenylalanine, proline, or a mixture thereof. In a more preferred embodiment, the sugar comprises trehalose, lactose, mannitol, sucrose, or a mixture thereof.

[0072] The formulations of the present invention are comprised of a physical blend of both spray-dried complex active particles, which constitute between 10-85% of the total formulation weight, and carrier particles, which constitute between 15-90% of the total formulation weight. In a preferred embodiment, the carrier particles are selected from the group including, but not limited to, lactose, mannitol, trehalose, raffinose, sucrose or microcrystalline cellulose or mixtures thereof.

[0073] The formulation of the present invention is produced by mixing the spray-dried composite particles with a carrier. This is typically 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 comprise lactose, mannitol, trehalose, raffinose, sucrose or microcrystalline cellulose or mixtures thereof.

[0074] The formulations of the present invention may be filled into a device or capsule. More preferably, the formulations of the present invention may be filled into a reservoir or blister-based device.

[0075] The formulation approach of the present invention provides a new area of ​​interest by combining two opposing formulation technologies for improved drug delivery, especially in highly resistant drug devices.

[0076] In summary, the process for producing a formulation according to the present invention typically involves the following three steps: a. Preparation of spray-dried composite particles; b. blending the spray-dried composite particles with carrier particles; c. Optionally, filling the final mixture into a suitable container (blister cavity, capsule or reservoir). may include.

[0077] Certain specific aspects and embodiments of the present invention will now be described in more detail with reference to the following examples. The examples are presented to aid in the understanding of the invention, but are in no way intended, and should not be considered as, limiting the scope of the invention. The reported experiments were carried out using a BUCHI Model B-290 Advanced Spray Dryer.

[0078] Example 1: The formulations were prepared according to the present invention. To prepare the spray-dried particles, the active ingredient was dissolved and the excipients were dissolved in a suitable solvent. The solution was atomized and dried using a laboratory-scale spray dryer (Buchi, model B-290) equipped with a three-fluid nozzle. Co-current nitrogen was used to facilitate drying after atomization. The spray-drying unit was operated in open cycle mode (i.e., without recirculation of drying gas). Figure 1 shows a schematic of the spray-drying design used.

[0079] Before feeding the solution to the nozzle, the spray-drying unit was stabilized with nitrogen to ensure stable inlet (T_in) and outlet (T_out) temperatures. After stabilization, the solution was fed to the nozzle by a peristaltic pump and atomized at the tip of the nozzle. The droplets were then dried in the spray-drying chamber with co-current nitrogen. The stream containing the dried particles was directed into a cyclone and collected at the bottom. The main operating parameters during the spray-drying process are summarized in Table 1. [Table 1]

[0080] The compounds obtained using the method of the present invention are amorphous solids that have a higher dissolution rate compared to the corresponding crystalline form. Several tests such as X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC) confirm the amorphous form of the compound.

[0081] The appearance of the atomized material was characterized by scanning electron microscopy (SEM), and a representative image of the resulting particles is shown in Figure 2.

[0082] The powder X-ray diffraction pattern of the spray-dried complex particles obtained according to the method described herein is shown in Figure 3, which is overlaid with L-leucine crystalline particles to confirm the peaks originating from L-leucine, the active ingredient being in amorphous form. Differential scanning calorimetry (DSC) from the resulting spray-dried complex particles is shown in Figure 4.

[0083] The complex active particles have been shown to have higher dissolution as measured by a Franz cell apparatus when compared to the crystal micronized particles (obtained by jet milling), see for example FIG. 5. The dissolution profiles of the jet milled and spray dried Remdesivir formulations were determined using a Franz cell diffusion apparatus previously described in the literature. Briefly, 2 mg of powder was weighed onto a filter and clamped onto each cell of a multi-station Franz cell (VB6, PermeGear Inc.). Each cell was contained within a heated water jacket that was preheated and then maintained at 37±0.05° C. throughout the experiment by a circulating water bath. 23 mL of HBSS solution was placed in the water bath in each cell at the start of the experiment and pumped at 5 mL / min into the inlet port of the Franz cell by a multi-channel peristaltic pump. The sampling port of the cell was connected to a second pump channel, and then the sample flow was returned to a 23 mL sink. Constant stirring of the dissolution medium and regeneration through the pump inlet port ensured a constant volume in the Franz cell, thus ensuring that the filter was uniformly wetted and sink conditions remained constant throughout the experiment. Samples of 0.6 mL were taken from the reservoir at pre-determined time intervals (up to 24 h) and analyzed in triplicate by HPLC.

[0084] The resulting complex active particles were blended with coarse lactose and the formulation composition is shown in Table 2. The spray dried complex particles and coarse lactose were blended in a low shear blender in two steps. The first step involved blending 66% w / w total lactose with 50% w / w total complex active particles at 96 rpm for 5 minutes. The second step involved the addition of the remaining lactose and complex active particles and blending for an additional 5 minutes at 96 rpm. [Table 2]

[0085] The resulting blend is loaded into a reservoir type device. The loading weight used was 31 mg. Loading was performed in an auger loading principle tool and no clogging was observed. The loading time was less than 40 seconds per cavity, much lower than the spray-dried composite particles alone. The aerodynamic performance of the spray-dried composite particles alone (A), the composite blend (B) (i.e. spray-dried composite particles and lactose) and the carrier-based blend (C) (i.e. lactose and micronized REM only) was evaluated by a Next Generation Impactor (NGI). The results are shown in Table 3. The ejected dose (ED) of the composite active particles alone was 2.5 mg compared to the composite blend, which was 7.9 mg. For the composite active particles alone, the majority of the powder remained inside the device (6.5 mg), while for the composite blend, only a few micrograms of powder remained inside the device (0.8 mg). This indicates that the composite particles alone are not sufficient to allow the flow through the reservoir device to fluidize and move the powder out. In vivo, this would be even worse for conditions where respiratory flow is impeded. The fine particle dose (FPD) of the complex blend is much higher than that of the complex active particle alone, 3.9 mg and 0.3 mg, respectively. This indicates not only a higher excretion rate, but also a higher dose that reaches the lungs and has a therapeutic effect. This fine particle dose is even higher compared to the common carrier-based blends (i.e., carrier-based blends, C) in which the active ingredient is micronized. [Table 3]

[0086] The results shown confirm that the formulations of the present invention (composite blends) have higher dosage efficiency, higher dissolution rates and higher fine particle doses when compared to equivalent crystalline forms. The formulations of the present invention also have higher discharge rates and fine particle doses when compared to spray-dried composite particles alone. Furthermore, the formulations of the present invention substantially resolve the processability issues seen during filling related to the high cohesiveness of spray-dried composite active particles.

[0087] Example 2: The formulations were prepared according to the present invention. To prepare the spray-dried particles, the active ingredient was dissolved and the excipients were dissolved in a suitable solvent. The solution was atomized and dried using a laboratory-scale spray dryer (Buchi, model B-290) equipped with a two-fluid nozzle. Co-current nitrogen was used to facilitate drying after atomization. The spray-drying unit was operated in open cycle mode (i.e., without recirculation of drying gas). Figure 1 shows a schematic of the spray-drying design used. Figure 1 shows a schematic of the spray-drying design used.

[0088] Before feeding the solution to the nozzle, the spray-drying unit was stabilized with nitrogen to ensure stable inlet (T_in) and outlet (T_out) temperatures. After stabilization, the solution was fed to the nozzle by a peristaltic pump and atomized at the tip of the nozzle. The droplets were then dried in the spray-drying chamber with co-current nitrogen. The stream containing the dried particles was directed into a cyclone and collected at the bottom. The main operating parameters during the spray-drying process are summarized in Table 4. [Table 4]

[0089] The compound obtained by using the method of the present invention is an amorphous solid with a higher dissolution rate compared to the corresponding crystalline form.The amorphous form of the compound can be confirmed by powder X-ray diffraction (XRPD).The powder X-ray diffraction pattern of the spray-dried composite particles obtained according to the method described herein is shown in Figure 6.

[0090] The resulting complex active particles were blended with coarse lactose and the formulation composition is shown in Table 5. The spray dried complex particles and coarse lactose were blended in a low shear blender in two steps. The first step involved blending 66% w / w total lactose with 50% w / w total complex active particles at 96 rpm for 5 minutes. The second step involved the addition of the remaining lactose and complex active particles and blending for an additional 5 minutes at 96 rpm. [Table 5]

[0091] The resulting blend is loaded into a reservoir type device. To maintain the nominal dose, the loading weight used was 20 mg for the complex particles and 30 mg for the carrier-based formulation. Loading was performed in an auger loading principle instrument and no clogging was observed. The aerodynamic performance of the spray-dried complex particles alone (A) and the complex blend (B) (i.e., spray-dried complex particles and lactose) was evaluated by a Next Generation Impactor (NGI). The results are shown in Table 6. The discharge volume (ED) is similar, but the fine particle fraction (FPF) is higher for the complex dispersion (B). The fine particle dose (FPD) of the complex active particles alone was 1.5 mg, in contrast to the complex blend, which was 2.6 mg. The fine particle dose (FPD) of the complex blend is higher than the complex active particles alone. This indicates a higher dose that reaches the lungs and has a therapeutic effect.

[0092] [Table 6]

[0093] DSC method:

Table 7

[0094]

Table 8

Claims

1. (i) Spray-dried agglomerable complex active particles in which each complex active particle contains an amorphous form of active pharmaceutical ingredient (API) material and an excipient, and (ii) Carrier particles an inhalable pharmaceutical composition comprising, The composite active particles and the carrier particles are blended as a physical mixture. A pharmaceutical composition comprising the complex active particles constituting 10 to 85% by weight of the pharmaceutical composition.

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

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

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the solubility and dissolution rate of the pharmaceutical active ingredient (API) material are higher than those of the crystalline isolated form of the API.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the composite active particles are more soluble than particles of the active pharmaceutical ingredient (API) material alone.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the complex active particles contain 10 to 90% by weight of a pharmaceutical active ingredient (API) material.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein the excipient comprises an amino acid, or a sugar, or a mixture of an amino acid and a sugar.

8. The pharmaceutical composition according to claim 7, wherein the amino acid comprises leucine, tryptophan, alanine, valine, isoleucine, trileucine, dileucine, methionine, phenylalanine, or proline, or a mixture of two or more thereof.

9. The pharmaceutical composition according to claim 7, wherein the amino acid comprises leucine, isoleucine, trileucine, or dileucine, or a mixture of two or more thereof.

10. The pharmaceutical composition according to claim 7, wherein the sugar comprises a disaccharide.

11. The pharmaceutical composition according to claim 7, wherein the sugar comprises trehalose, lactose, mannitol, or sucrose, or a mixture of two or more thereof.

12. The pharmaceutical composition according to claim 7, wherein the sugar comprises trehalose, lactose, or sucrose, or a mixture of two or more thereof.

13. The pharmaceutical composition according to any one of claims 1 to 3, wherein the complex active particles constitute about 50 to 85% by weight of the pharmaceutical composition.

14. The pharmaceutical composition according to any one of claims 1 to 3, 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.

15. The pharmaceutical composition according to claim 14, wherein the carrier particles comprise lactose, lactose monohydrate, or a mixture of lactose and lactose monohydrate.

16. The pharmaceutical composition according to any one of claims 1 to 3, wherein the carrier particles constitute about 15 to 90% by weight of the pharmaceutical composition.

17. The pharmaceutical composition according to any one of claims 1 to 3, wherein the carrier particles constitute about 15 to 50% by weight of the pharmaceutical composition.

18. The pharmaceutical composition according to any one of claims 1 to 3, wherein the carrier particles have an aerodynamic median mass (MMAD) greater than 25 μm.

19. The pharmaceutical composition according to any one of claims 1 to 3, wherein the carrier particles have an aerodynamic median mass (MMAD) of 50 μm to 100 μm.

20. A method for preparing a pharmaceutical composition according to any one of claims 1 to 3, i) A step of preparing a solution of a pharmacokinetic active ingredient (API) material and an excipient, which may be separate or combined solutions, and spray-drying them to provide agglomerable complex active particles, wherein each complex active particle contains the pharmacokinetic active ingredient (API) material and excipient in amorphous form. ii) A step of blending the spray-dried agglomerating composite active particles with carrier particles to form a physical mixture. Includes, A method wherein the complex active particles constitute 10 to 85% by weight of the pharmaceutical composition.

21. A method for preparing the pharmaceutical composition according to claim 20, comprising performing a post-drying or conditioning step after step (i) or after step (ii), or both.

22. A method for preparing the pharmaceutical composition according to claim 20, wherein the diameter distribution of the composite active particles is controlled to a Dv50 of 5 μm or less.

23. A method for preparing the pharmaceutical composition according to claim 20, wherein step (ii) involves a high-shear or low-shear process for blending.

24. A blister pack or a series of blister packs or one or more capsules comprising the pharmaceutical composition according to any one of claims 1 to 3, for use in a dry powder inhaler.

25. A dry powder inhaler comprising the blister agent or a series of blister agents or one or more capsules according to claim 24.

26. A dry powder inhaler, which is a reservoir device containing the pharmaceutical composition according to any one of claims 1 to 3.

27. A pharmaceutical composition according to any one of claims 1 to 3, for use as a pharmaceutical.

28. The pharmaceutical composition according to claim 27 for use in the treatment of lung conditions.

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