CROSS REFERENCE TO RELATED APPLICATIONS

This application is a filing under 35 U.S.C. 371 of International Application No. PCT/GB2016/053158 filed Oct. 12, 2016, entitled “Method of Production of Inhalable Composite Particles using a Three-Fluid Nozzle” which claims priority to Portuguese Patent Application No. 108885 filed Oct. 12, 2015, which applications are incorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION

The present invention is in the technical field of drying methods for pharmaceutical compounds. More particularly, the present invention is in the technical field of spray drying applied to the production of inhalable composite particles comprising an active pharmaceutical ingredient (API) wherein the potential solubility differences and/or chemical incompatibility existing between the API and the excipient can be challenging when preparing a single solution. The present invention consists of a method of production of composite particles comprising an active agent and an excipient using spray drying apparatus having a three-fluid nozzle. The active agent can be one or more APIs and can be poorly water soluble, and the excipient can be one or more excipients.

In the pharmaceutical industry there is a wide variety of drug delivery platforms, namely for oral delivery through tablets, pills, capsules, elixirs, or the like; for topical, injectable, ocular and orally or nasally inhaled delivery among others. Pharmaceutical interest in the delivery of drugs to the lungs has been increasing, either to treat local diseases such as asthma, chronic obstructive pulmonary diseases (COPD), emphysema and cystic fibrosis, or for systemic drug delivery to treat diabetes, osteoporosis, cancer, neurological diseases (including pain) or prophylaxis of a disease, among others. Drug delivery to the lungs presents several advantages due to the advantageous physiological characteristics of the lungs such as low enzymatic activity and thin epithelial barrier to absorption. Some of the advantages are the rapid onset of drug action and bioavailability, while avoiding the first pass metabolism which reduces the total drug load required and minimizes the adverse side effects, leading to a more efficient therapy for the patients.

There are many types of inhaler devices able to deliver the APIs as a dry powder or in a liquid, namely, dry powder inhalers (DPIs), pressurized metered dose inhalers and nebulizers. The DPI can be active or passive and the drug can be administered as a unit-dose or a multi-dose reservoir, actuated at different flowrates, pressures and aerosolization mechanisms according to the device design.

The present invention produces a DPI formulation using a new production method which utilizes a spray drying apparatus.

When developing DPI formulations, the API particle size (PS) required is usually between 0.5 and 5 μm. These APIs are often highly potent, which means that only a small dose is required to achieve the therapeutic effect, usually below 500 μg. Due to the API small particle size, the particles tend to be very cohesive due to their high surface free energy, which frequently leads to a poor aerosolization performance. Some of the strategies employed to mitigate this problem and to ensure improved delivery efficiency consist in the addition of excipients to manipulate the powder interfacial forces, in order to reduce the API cohesiveness and to avoid particle agglomeration, namely:a) Blending the size-reduced API (0.5<PS<5 μm) with large carrier particles. The most commonly used and well-known carrier is lactose monohydrate. The API particles adhere to the carrier surface and upon oral inhalation of the formulation detach from the carrier surface. The particles are then deposited on the physiologically relevant stages of the lungs, while the carrier particles deposit at the mouth and throat. This method is known as “carrier-based”;b) Production of composite particles containing one or more excipients and one or more APIs. The composite particles are produced with a PS between 0.5 and 5 μm. The excipients are selected in order to reduce the particle cohesiveness in order to enable a good powder aerosolization. Upon inhalation, the particles flow through the respiratory tract and deposit in the physiologically relevant stages of the lungs. This is known as the “composite particle” method, where each particle comprises both excipient and drug.

Although both methods are used, the carrier-based method can present several drawbacks such as uniformity of the delivered dose issues and, sometimes, poor aerosolization efficiency (low fine particle fraction, that is, a low amount of API with an aerodynamic diameter of below 5 μm that is able to reach the deep lung). The use of the composite particles method has been gaining momentum, where the particles with a PS within 0.5 and 5 μm already contain the API and the excipients which improve the aerosolization and ensure a uniform API delivery to the lungs. Additionally, this method enables the processing of thermo-sensitive APIs such as biomolecules, since the particle engineering technologies employed are typically gentle. The production of composite particles using spray drying technology is a well-known formulation method that presents several advantages when compared with conventional encapsulating techniques like water-in-oil double emulsion and solvent evaporation coacervation methods. Although new encapsulating technologies like interfacial solvent exchange and dual-capillary electrospray have been used, the encapsulation process is still too complex. Spray drying is a simple, flexible, single step, optionally continuous and easily scalable process, with clear advantages over the previously described methods.

In a spray drying process, one or more components are dissolved or suspended in a solvent or mixture of solvents. In the conventional approach, the feedstock (comprising the excipients dissolved and the API dissolved or suspended, either in a single solvent or in a mixture of solvents) passes through a nozzle where the droplets are formed; and as the droplets contact with a hot gas stream, the solvent evaporates and dry particles are formed, which will be collected downstream through a cyclone, filter bag or any other suitable collecting system.

Generally accepted inhalation excipients, such as sugars, salts, amino acids, sugar alcohols, and polymers are usually water soluble and poorly soluble in the vast majority of the organic solvents that have practical application in spray drying. On the other hand, among the diversity of commercial APIs for inhalation as well as new chemical entities in research, the majority of the molecules exhibit poor water solubility. Furthermore, typical inhalation spray drying processes tend to favor aqueous feedstock to minimize the need for additional powder processing to comply with residual solvents limits. Hence, in order to perform spray drying of a pharmaceutical composition for inhalation:1) there might be challenges to find a pharmaceutically acceptable solvent system that solubilizes both the API and the excipient(s);2) even if point 1) can be overcome, some APIs may present chemical incompatibility towards the required mixture of aqueous and organic solvents and/or there might be limitations in terms of the maximum amount of API that can be solubilized, with a negative impact in process throughput and flexibility.3) Although points 1) and 2) can be overcome by working with an API nanosuspension (that would be microencapsulated by the dissolved excipient phase, upon drying), size-reduction to the nano size range involves complex, expensive and laborious techniques that, in many cases, may prove unsuccessful.

When preparing a pharmaceutical composition for inhalation, by spray drying from a solution, the nozzles that are most commonly used are the two-fluid nozzles since the remaining types of nozzles (pressure, rotary and ultrasonic) are less efficient in generating the small droplet/particle size required. Several patents and articles contributed to the increased knowledge in the particle engineering field, which consisted in combinations of formulations and spray drying process parameters, enabling the production of inhalable pharmaceutical composite particles.

Four main patents contributed to the increasing knowledge regarding the combination of formulation and spray drying process parameter conditions. In the following patents, inhalable pharmaceutical powders were produced using a spray drying unit where the feed solution was delivered via a single feed stream.

Lipp et al., US2013/0266653 A1, refers to the production of spray dried respirable dry powder formulations for local or systemic delivery to the lungs of a pharmaceutical active agent containing one or more monovalent metal cation salts and optionally carbohydrates and/or amino acids as excipients. This patent provides methods to prepare dispersible composite particles. However, this method consists of the preparation of a single solution containing both API(s) and excipient(s) in a single solvent/co-solvent system, which limits the API/excipient system composition due to the solubility limitations of the selected solvent system.

In Mcintosh et al., WO 2013/016754 A1, the spray-drying of an aqueous solution and/or suspension comprising a biologically active protein or peptide, with one or more mono, di- or polysaccharides and/or amino acids, and L-leucine is claimed. The powders were able to reach high fine particle fractions (FPF) of about 73%. However, the process is limited to the spray drying of aqueous solutions containing preferably a biological active agent, indicating that there is no provision for preparing pharmaceutical active agents with poor water solubility.

In Vehring et al., U.S. Pat. No. 7,862,834 B2, a pharmaceutical dry powder formulation comprising an excipient encapsulating the active agent, where the excipient is more soluble in water than the active agent is claimed. Here, the formulation is produced using a solution comprising a first solvent, a second solvent, an active agent and an excipient where the second solvent is less polar than the first solvent; and, in this way, by removing the first and second solvents, particles comprising the active agent encapsulated by the excipient are yielded. In this invention, preferable encapsulating agents include L-leucine. However, in Vehring et al., the pharmaceutical dry powder inhaler composition limits the degree of encapsulation because a single solution comprising the API and excipient in a single solvent/co-solvent system is used. This decreases the process flexibility and the API/excipient system selection.

Vehring et al., U.S. Pat. No. 8,668,934 B2, claims a method of preparing a pharmaceutical formulation comprising: providing a single solution comprising a first solvent, a second solvent, an active agent and an excipient, where the second solvent is less polar than the first, and the excipient is more soluble in the first solvent than the active agent. In this patent, a single solution is delivered to the spray dryer for the production of encapsulated composite particles. In Vehring et al. the production method comprises the preparation of a single solution where the API and excipient(s) with different solubilities are all dissolved in a single solution using a single solvent/co-solvent system. This limits the range of API and excipient amount that can be incorporated in the solution, which in specific cases where the API is poorly water soluble can represent a hurdle for the production of inhalable composite particles.

The above-mentioned prior art patents are all based on spray drying pharmaceutical composite particles by delivering a single solution/suspension to the spray drying chamber, using a standard nozzle. These prior art patents share the same constraint, which is to dissolve the required amount of API(s) and excipient(s) with different solubility requirements in one solvent/co-solvent system, all in the same solution. This is particularly challenging for inhalation formulations since a large number of APIs present poor water solubility while the majority of the excipients are water soluble.

Alternatively, an external three-fluid nozzle has been used. Such external three fluid nozzles are composed by two liquid and one gas stream which are concentrically disposed to deliver the solutions outside the nozzle channels to the spray drying chamber. The three-fluid external nozzle is part of a new class of nozzles that are already known for the production of composite particles.

However, most of these applications are for oral or injectable purposes and most of them consist of spray drying the API particles in suspension, requiring the coupling of a size-reduction process to the spray drying process.

Kirkpatrick et al., U.S. Pat. No. 4,610,760, discloses a method of atomizing liquids, more specifically a three-fluid nozzle to atomize high viscosity and difficult-to-spherize liquids to be spray dried. However, the problem Kirkpatrick solves here is one of viscosity, which is overcome by using not one but two of the three-channels to deliver a gas stream. In this case there is no need to keep two solutions separate because only one exists.

York et al. [1], 1999, also describes a three-fluid nozzle used with supercritical fluids where a solution and a co-solvent are separately fed with the objective to control the crystallization mechanism and not partial particle encapsulation as in the present case.

Kondo et al. [2], discloses the production of sustained release microcapsules using a three-fluid nozzle. In this study, microparticles were prepared by spraying a drug suspension in the inner channel composed of an Ethenzamide (suspended API) and by Hypromellose 2910 (suspending agent) in water and an ethylcellulose solution in ethanol in the outer channel for coating. This case showed that the three-fluid nozzle is useful as a microencapsulation method when using suspended APIs with a suspending agent in the inner channel, however contrary to the present invention, it does not overcome the poor drug solubility challenge since the drug is suspended, which can also be performed using a two-fluid nozzle by controlling the solvents used and the drying kinetics.

Feng et al. [3], also makes use of a three-fluid nozzle where two of the channels are used to deliver solutions. One contains a water soluble protein (lysozyme) and a stabilizing sugar, both dissolved, and the second delivers dissolved poly lactic-co-glycolic acid (PLGA). As in Kondo et al. the objective is to perfectly coat and protect the protein and sugar core particles with the PLGA.

As described in connection with the previous authors, Pabari et al. [5] also describes the use of a three-fluid nozzle to produce diclofenac sodium (DFS) encapsulated by a polymer (ethyl cellulose) without reference to potential and unwanted solvent interactions.

Tanno et al., US 20050158386 A1 prepared a pharmaceutical solid dispersion using a three-fluid nozzle in a fluidized-bed granulation machine. The solid dispersion is produced by feeding into the inner channel a solution of a poorly soluble drug dissolved in a plasticizer and into the outer channel an aqueous solution and/or water dispersion of a water-soluble polymer. The goal of this strategy is to improve drug dissolution and the uniformity of granulations or coating films. This patent is distinct from the present invention where a glass former is used to stabilize the drug and the shell former improves the powder aerodynamic performance and enhances the drug protection; therefore focusing in a different field of application (inhalation delivery), ruled by different mechanisms and where very distinct challenges and goals are intrinsic.

In Gordon et al., US 20020132011 A1 a method of preparing dry powders with hydrophobic and hydrophilic components is presented using an internal mixture coaxial nozzle in a spray drying apparatus. In the invention, the two components are separately dissolved in different solvents and simultaneously directed to the coaxial nozzle, mixed in an internal chamber (internal mixture nozzle) and then delivered to the spray dryer drying chamber. However, the method of Gordon et al. presents potential problems such as: i) potential product precipitation and nozzle blockage inside the nozzle due to solubility or chemical incompatibility of the components; ii) liquid-liquid phase separations which may cause powder uniformity issues; and/or, iii) limited control over the powder properties (e.g. internal core and shell structure), and limited control over the encapsulation process.

Therefore, it is clear that the state of the art in the use of three-fluid nozzles is essentially concerned with encapsulation for protection purposes and not with the need to segregate different solutions so as to avoid limitations of optimum solubilisation.

It is also clear that the state of the art above does not provide teaching on using three-fluid nozzles for the preparation of pharmaceutical compositions of poorly water soluble active agents for inhalation purposes which requires very specific properties that the prior art does not provide.

In contrast, the present invention describes a production method where use of a three-fluid external mixing nozzle is essential, in that it keeps the two solutions apart, until the moment where they are co-spray dried, contrary to an internal mixing nozzle where both solutions are mixed inside the nozzle. Moreover, the present invention discloses a production method which consists of the use of an external three-fluid nozzle for the production of composite particles for inhalation purposes by delivering to the drying chamber two independent solutions that allow the control of the particle properties such as size, morphology and surface coating without the typical API/excipient solubility and/or chemical compatibility limitations.

The present invention overcomes some of the shortcomings identified in the art, by i) specifically addressing the API/excipients solubility limitations, which expands the API and excipients range than can be used, contributing for higher solids throughput since a more concentrated API/excipient solution can be prepared; ii) allows spray drying of compounds that are insoluble in the same solvent system; iii) allows spray drying of compounds that are chemically incompatible in the same solvent system; iv) enables a better control over the particles properties such as the microencapsulation degree; v) simplifies the overall process by eliminating the need to couple a size-reduction process with the active agent; vi) streamlines scale-up of the process; and vii) reduces the amount of organic solvents required to solubilize the active agent.

The present invention solves the problem of producing inhalation formulations where a large number of APIs present poor water solubility while the majority of the excipients are water soluble. It has been found to be advantageous to use two separate solutions, one for the API(s) and other for the excipient(s). It has been found to be advantageous to use an external three-fluid nozzle (i.e. two channels for the solutions and one for the drying gas) in the spray drying apparatus. Another advantage of the external three-fluid nozzle of the present invention is the fine control over the degree of encapsulation and higher flexibility by independently manipulating the API and excipient solutions composition and relative proportion fed to the spray dryer. The inhalable powders produced can be partially encapsulated, as observed inFIG. 1, where a different number of fragmented particles or particles with holes at the surface are observed across different trials/operating conditions. Controlling the degree of encapsulation is particularly advantageous for patients with acute lung disease conditions that demand a quick API burst on the target site, followed by a more sustained release.

Additionally, by using an external mixture nozzle, the mixing of the components occurs externally, thus enabling the use of higher solids content which is particularly critical and advantageous for the process throughput and economic viability, especially in the inhalation industry where the final product is extremely expensive.

SUMMARY OF THE INVENTION

The present invention relates a method of production of inhalable composite particles by spray drying two independent solutions comprising the API and excipient separately, by means of a three-fluid nozzle inside the drying chamber. This innovative concept allows spray drying of pharmaceutical compositions comprising API and excipients that are insoluble in the same solvent composition, enabling higher flexibility in terms of process parameters and final inhalable particle properties, while assuring the maintenance of an appropriate aerodynamic performance for pulmonary delivery, which would not be possible through a conventional spray drying process.

According to a first aspect of the present invention there is provided a method of preparing a pharmaceutical formulation, the method comprising: providing a first solution comprising a first solvent and an active agent, providing a second solution comprising a second solvent and at least one excipient; and removing the first and second solvents by simultaneously drying both the first and second solutions in a spray dryer having an external mixing three-fluid nozzle that produces one or more particles comprising both the active agent and the one or more excipient. In a preferred aspect the pharmaceutical composition is suitable for inhalation.

Preferably, the one or more excipient is more soluble in water than the active agent.

Preferably, the one or more particles have a mass median diameter of less than 5 μm. In particular, particles having a mass median diameter of between 0.5-5 μm, alternatively between 1-4 μm. The mass median diameter of the particles can be measured using a method known in the art such as use of a scanning electron microscope (SEM) or laser diffraction.

Preferably, the one or more particles comprise excipient at least partially encapsulating the active agent. The one or more particles may comprise excipient totally encapsulating the active agent.

At least one excipient is provided. One excipient may be a stabilizing agent. The at least one excipient may comprise one or more component chosen from the group comprising: amino acids; sugars; or mixtures thereof. The sugar may be selected from lactose, trehalose, or raffinose. The amino acid may be selected from leucine, iso-leucine, tri-leucine or isomers thereof. Any of the above-mentioned sugars may be combined with any of the above mentioned amino acids.

The excipient may comprise one or more components; preferably trehalose and leucine.

The first solvent may be an organic solvent or a mixture containing at least an organic solvent and water.

The second solvent may be water or a mixture containing at least water and an organic solvent.

The external three-fluid nozzle may comprise an inner channel and an outer channel, and preferably the first solution is fed to the inner channel and the second solution is fed to the outer channel. Alternatively, the first solution may be fed to the outer channel and the second solution fed to the inner channel. Alternative arrangements of external three-fluid nozzle as known in the art may also be used according to the method of the present invention.

Preferably, the feed rate of the second solution is always higher than the feed rate of the first solution. This ensures that the API is encapsulated or coated by the excipient.

Preferably, the active agent requires at least 30 parts of water to dissolve one gram of solid at a temperature of 20° C.

According to a second aspect of the present invention there is provided a pharmaceutical composition obtainable by the above-mentioned method.

