High-density composite active particles comprising beta-lactoglobulin and API, compositions comprising same, and methods for the manufacture thereof

Abstract

A pharmaceutical composition comprising composite active particles that comprise β-lactoglobulin and at least one active pharmaceutical ingredient (API) is provided, with methods for producing and using same in the administration of the API to a subject. The composite active particles have a tapped density of at least about 0.35 g / cm3.

Description

[0001] HIG H-DENSITY COMPOSITE ACTIVE PARTICLES COMPRISI NG BETALACTOGLOBULI N AND API, COMPOSITIONS COMPRISI NG SAME, AND METHODS FOR TH E MANUFACTURE TH EREOF

[0002] Field of the Invention

[0003] The invention relates to composite active particles comprising p-lactoglobulin and at least one active pharmaceutical ingredient, and compositions comprising the composite active particles, as well as to methods for manufacturing and using same.

[0004] This invention relates to compositions and methods for the manufacture of high-density composite active particles comprising p-lactoglobulin (BLG) and at least one active pharmaceutical ingredient (API), wherein the method comprises first providing a solvent system comprised of a first solvent that is an aqueous solvent or organic solvent; a second solvent that is an organic solvent; at least one API dissolved in the solvent system; and BLG at least partially suspended in the solvent system and then removing the solvents to form composite active particles of BLG and API having a high tapped density. The composite active particles are suitable for use in pharmaceutical compositions for inhalation or nasal administration, where the delivery of a high payload of API through only a few actuations, or even a single actuation, of a delivery device is achievable.

[0005] Background of the Invention

[0006] Dry-powder pharmaceutical compositions comprising composite active particles are becoming a widespread solution for the delivery of APIs to the lungs or nasal cavity. Dry-powder inhalers (DPIs) are typically used to deliver such dry-powder pharmaceutical compositions for the treatment of chronic respiratory diseases such as asthma or chronic obstructive pulmonary disease. Nevertheless, in recent years, dry-powder pharmaceutical compositions have received considerable attention for acute respiratory treatments such as treatment of infectious diseases or delivery of vaccines, among others. This has led to an increased interest in delivering high payloads of APIs to patients via inhalation or nasal delivery, such as antibiotics, antivirals, vaccines, proteins, peptides, oligonucleotides, and other drugs, that can act locally and systemically upon being administered through the lung or nasal cavity.

[0007] Conventionally, the composite spray-dried particles used in dry-powder pharmaceutical compositions have been engineered to be of low density (< 0.4 g / cm3), with porous surface properties to minimize inter-particulate forces. This maximizes the aerosol dispersibility of these engineered particles — achieving targeted delivery while minimizing interparticle cohesive forces. Such engineered particles show improved drug delivery efficiency to the lungs; however, the deliverable dose of API for these engineered particles is limited due to their low density and poor packing properties. In these approaches, it is important the particle density be kept to a minimum to engineer particles with an optimal aerodynamic profile. The disadvantage of this approach is that multiple actuations of the DPI and multiple inhalations are needed to deliver a therapeutic dose of the API per treatment cycle. For example, to deliver the intended dose of API (tobramycin) to the lungs, a patient, twice a day, must actuate and inhale four Tobi Podhaler® capsules (28 mg of tobramycin per capsule) to treat Pseudomonas aeruginosa pulmonary infections in cystic fibrosis patients. Likewise, with Bronchitol®, to deliver the intended dose of mannitol to the lungs, a patient, twice a day, must actuate and inhale ten Bronchitol® capsules (40 mg of mannitol per capsule) to improve lung function in adults with cystic fibrosis.

[0008] Therapies requiring high numbers of actuations per treatment cycle can easily be impractical due to difficulties in ensuring patient compliance. Similarly, inefficient delivery of API, due to high numbers of actuations, directly into the lung may lead to adverse effects, such as toxicological / safety risk, caused by the API being delivered elsewhere in the body, such as being deposited on the oro-laryngeal or gastrointestinal tract. Hence, drug payload — the quantity of drug that can be delivered in a single actuation / inhalation — is important for patient compliance and consequent efficacy. Therefore, formulation development approaches to increase the density of the dry-powder formulations to enable packing of higher fill weights in the DPI capsules, while maintaining highly efficient aerosol performance is needed.

[0009] In WO2019 / 145897, a shell former, leucine or trileucine, was used to obtain powders having high tapped densities and high emitted doses. However, this approach required a careful particle engineering approach that required slow-drying times and use of minimal amounts of the shell former (< 10% by weight) so as to allow time for the leucine / trileucine shell to form around the API. Too much of the shell former resulted in powders that were insufficiently dense.

[0010] Accordingly, there remains a need in the art for new pharmaceutical compositions, and in particular those that are suitable for inhalation or nasal delivery.

[0011] Summary of the Invention

[0012] In a first aspect the present invention provides a pharmaceutical composition comprising composite active particles, wherein the composite active particles comprise p-lactoglobulin (BTG) and at least one active pharmaceutical ingredient and wherein the composite active particles have a tapped density of at least about 0.35 g / cm3.

[0013] In a further aspect the present invention provides a method of making a pharmaceutical composition comprising: a. providing a solvent system comprising: (i) at least two solvents, wherein there is a first solvent that is comprised of one or more aqueous or organic solvents and there is a second solvent that is comprised of one or more organic solvents; (ii) at least one active pharmaceutical ingredient mixed in the solvent system; and (iii) BLG at least partially suspended in the solvent system; b. removing the solvents from the solvent system to produce composite active particles that comprise BLG and at least one active pharmaceutical ingredient, wherein the composite active particles have a tapped density of at least about 0.35 g / cm3; c. collecting the composite active particles.

[0014] In another aspect the present invention provides a method of making a pharmaceutical composition comprising: a. providing a first solvent that is comprised of one or more aqueous or organic solvents; b. mixing BLG in the first solvent to form a mixture of BLG and first solvent; c. providing a second solvent that is comprised of one or more organic solvents; d. mixing the second solvent with the mixture of BLG and first solvent to form a solvent system comprising the first solvent, the second solvent, and aggregates of BLG at least partially suspended in the solvent system; e. adding at least one active pharmaceutical ingredient into the solvent system by adding the at least one active pharmaceutical ingredient into one of the following: the first solvent; the mixture of BLG and first solvent; the second solvent; or the mixture of first solvent, second solvent, and BLG; f. removing the solvents from the solvent system to produce composite active particles that comprise BLG and at least one active pharmaceutical ingredient, wherein the composite active particles have a tapped density of at least about 0.35 g / cm3; g. collecting the composite active particles.

[0015] In a still further aspect the present invention provides a method of making a pharmaceutical composition comprising: a. providing a first solvent that is comprised of one or more aqueous or organic solvents; b. providing a second solvent that is comprised of one or more organic solvents; c. mixing BLG in the second solvent to form a mixture of BLG and second solvent; d. mixing the first solvent with the mixture of BLG and second solvent to form a solvent system comprising the first solvent, second solvent, and aggregates of BLG at least partially suspended in the solvent system; e. adding at least one active pharmaceutical ingredient into the solvent system by adding the at least one active pharmaceutical ingredient into one of the following: the first solvent; the second solvent; the mixture of BLG and second solvent; or the mixture of first solvent, second solvent, and BLG; f. removing the solvents from the solvent system to produce composite active particles that comprise BLG and at least one active pharmaceutical ingredient, wherein the composite active particles have a tapped density of at least about 0.35 g / cm3; g. collecting the composite active particles.

[0016] In other aspects the present invention provides a pharmaceutical composition, prepared by the methods described herein.

[0017] In still other aspects the present invention provides a container comprising the pharmaceutical composition or an inhaler device comprising the pharmaceutical composition or the container. In further aspects the present invention provides a method of administering the pharmaceutical composition of the invention, wherein the pharmaceutical composition is administered via inhalation and a method of administering the pharmaceutical composition of the invention, wherein the pharmaceutical composition is nasally administered.

[0018] In addition, in still further aspects, the present invention provides the pharmaceutical composition described herein for use in medicine, optionally wherein the use comprises administering via inhalation or administering nasally The present invention also provides use of the pharmaceutical composition for the manufacture of a medicament for use in delivering or administering the API to the subject.

[0019] These and other aspects will be described further below.

[0020] In contrast to the disclosure of WO 2019 / 145897 described above, in the present invention, BTG is not a shell former. In fact, any suitable amount of BTG may be combined with API to form sufficiently dense composite active particles that maintain efficient aerosol performance, as demonstrated in Example 2 (demonstrating the production of highly dense composite active particles with excellent aerosol performance wherein the composite active particles comprise 1.6 wt% of API (fluticasone) and 98.4 wt% of BEG).

[0021] BLG is a naturally occurring biopolymer and the main component of whey protein. BLG has been previously studied as an excipient that can stabilize amorphous drug forms and consequently improve the solubility and dissolution of the drug in oral formulations, which typically have particle size distributions greater than 20 pm. In contrast to the disclosures of WO2017186889, WO2018113890, WO2021110983A1, or WO2022 / 258625A1, in the present invention the composite active particles are produced using solvent systems that are selected based on the solubility of BLG and the API used, and based on the intended aerodynamic performance of the formulated particles. In contrast to WO2017186889 and W02021110983A1, where it is claimed that maintenance of BLG structure and BLG purity is key for the formation of stable amorphous dispersions, the present invention leverages conformational changes and modifications induced to BLG by the conditions of the solvent system to form distinct BLG aggregation profiles, which results upon drying in the formation of composite active particles with high tapped densities (> 0.35 g / cm3, or > 0.4 g / cm3) and particle size distributions (Dv90 from <3 pm to >17 pm) suitable for inhalation or nasal delivery that provide a tuned aerodynamic performance of the resulting pharmaceutical compositions.

[0022] The present invention is not a common spray-dried composition, as the size of the composite active particles in the present invention are not varied by changing the droplet size in the spray dryer. Instead, the size of the composite active particles of the present invention are varied by obtaining distinct BLG aggregation profiles in the solvent system (via the use of different combinations of first and second solvents and / or by controlling the order in which BLG is mixed into the first or second solvent and the order in which the first and second solvent are mixed with each other).

[0023] The composite active particles provided by the present invention differ significantly from the prior art in at least two major features. The high tapped densities of the composite active particles of the present invention allow for the administration of high API payloads which is mandatory in the case of pharmaceutical compounds for acute treatments, such as, but not limited to, antibiotics, antivirals, vaccines, proteins, peptides and nucleic acids. On the other hand, the composite active particles of the present invention contain a BLG excipient that can be tunably aggregated in the solvent system to maximize the fine particle fraction by decreasing the particle size and increasing the flowability, dispersibility and aerosolization of the composite active particles. In addition, the particle size and fine particle fraction of the composite active particles can be varied to target nasal delivery or distinct pulmonary regions by changing the degree of BLG aggregation in the solvent system.

[0024] Description of Drawings

[0025] Figure 1 - Illustrates a standard spray-drying set up used for producing the composite active particles of the present invention.

[0026] Figures 2A to C - Aerodynamic performance of composite particles of BLG placebo prepared in distinct solvent systems as described in Example 1. Figures show the fine particle fraction of the emitted dose (FPF) in % (Figure 2A), the emitted dose (ED) in mg (Figure 2B), and the fme particle dose (FPD) in mg (Figure 2C) for different w / w percentages of solvent 1 used in the preparation of the composite particles. (Solvent 1 in this context is the solvent that the BEG is first mixed with - either organic solvent or water, as described in Example 1. DCM - dichloromethane; MeOH - methanol; EtOH - ethanol; H2O - water.)

[0027] Figures 3A to C - Correlation between aerodynamic performance and particle size distribution of composite particles of BLG placebo prepared in distinct solvent systems as described in Example 1. Figures show the fme particle dose (FPD) in mg against DvlO in pm (Figure 3A), Dv50 in pm (Figure 3B), and Dv90 in pm (Figure 3C). (As per Figures 2A to C, solvent 1 in this context is the solvent that the BLG is first mixed with - either organic solvent or water, as described in Example 1. DCM - dichloromethane; MeOH - methanol; EtOH - ethanol; H2O - water.)

[0028] Figure 4 - Correlation between aerodynamic performance and density profile of composite particles of BLG placebo and BLG:fluticasone furoate prepared in distinct solvent systems as described in Example 2. The Figure shows the fme particle fraction of the emitted dose (FPF) in % against the tapped density of the composite particles in g / cm3.

[0029] Figures 5A to C - Aerodynamic performance of high fill weight trials of composite active particles of BLG: tobramycin in both a capsule-based delivery system with gravimetric filling and dosator filling at 3 compression levels and in a depot delivery system (Twin Max) as described in Example 3. The Figures show the emitted dose (ED) as a % of the fill weight (Figure 5A), the estimated fme particle dose (FPD) in mg (Figure 5B), and the fme particle fraction of the emitted dose (FPF) in % (Figure 5C), all against the fill weight in mg.

[0030] Figures 6A to G - X-ray powder (XRP) diffractograms of composite active particles of BLG: fluticasone furoate and BLG: tobramycin at increasing drug loads of each API and with supplementation of glass former excipients as described in Example 4. Figure 6A provides the diffractogram for a control composite particle comprising trehalose and leucine (50 / 50 spray dried dispersion (SDD)) with a 1.6% drug load (DL) of fluticasone furoate, i.e., a low dose of the API. Figures 6B, 6C and 6D provide the diffractograms for composite particles according to the invention comprising BLG and 1.6 % DL of fluticasone furoate (low dose API), 75 % DL of fluticasone furoate (high dose API), and 75 % DL of fluticasone furoate with trehalose (high dose API + glass former), respectively. Figures 6E to 6G provide the diffractograms for composite particles according to the invention comprising BLG and 25% DL of tobramycin, 50% DL of tobramycin, and 75% DL of tobramycin, respectively (all high doses of the API).

[0031] Figures 7A to D - Alberta Idealized Nasal Inlet (AINI) nasal deposition profile of composite active particles of BLG:fluticasone furoate as described in Example 5. Figures show mean values obtained (with SD of the mean marked) from three replicates. Figure 7A shows the amount of fluticasone furoate recovered from each location (in pg) per actuated capsule (PS - pre- separator). Figure 7B shows the amount recovered from each location as a % of the emitted dose. Figure 7C shows the fluticasone furoate emitted dose and recovered mass balance (both in %) . Figure 7D shows the results represented in Figure 7B grouped by region.

[0032] Figures 8A to F - Properties and aerodynamic performance of spray-dried composite active particles of BLGflevodopa and BLG:vancomycin at increasing drug loads using capsule-based delivery system (Plastiape RS 5) with gravimetric filling (48 mg target fill weight) as described in Example 6. Figures show tapped density in g / cm3, particle size distribution (Dv50) in pm, emitted dose in %, fine particle fraction (FPF) of emitted dose in %, and estimated fine particle dose (FPD) in mg / capsule, all against drug load in %, Figures 8 A to 8E, respectively. API estimated fine particle fraction was calculated based on drug load and SDD fine particle fraction. Figure 8F shows the correlation between fine particle fraction (FPF) of the emitted dose in % and Dv90 in pm.

[0033] Detailed Description of the Invention

[0034] According to a broad aspect of the present invention, herein is provided a pharmaceutical composition comprising composite active particles, wherein the composite active particles comprise P-lactoglobulin (BLG) and at least one active pharmaceutical ingredient (API) and wherein the composite active particles have a tapped density of at least about 0.35 g / cm3, or at least about 0.4 g / cm3.

[0035] In a further broad aspect of the present invention, there is provided a method to make a pharmaceutical composition comprising: a. providing a solvent system comprising: (i) at least two solvents, wherein there is a first solvent that is comprised of one or more aqueous or organic solvents and there is a second solvent that is comprised of one or more organic solvents; (ii) at least one active pharmaceutical ingredient mixed in the solvent system; and (iii) BLG at least partially suspended in the solvent system; b. removing the solvents from the solvent system to produce composite active particles that comprise BLG and at least one active pharmaceutical ingredient, wherein the composite active particles have a tapped density of at least about 0.35 g / cm3, or at least about 0.4 g / cm3; c. collecting the composite active particles.

[0036] Although any suitable solvent removal process may be used, the solvent removal step preferably comprises spray drying. Other solvent removal processes that may optionally be used include spray-freeze-drying or freeze drying (lyophilization), flash mill drying or mill drying, electrostatic spray drying, and similar.

[0037] In general, the present invention relates to a pharmaceutical composition that enhances the dosing efficiency of an API to the central or peripheral lung regions or the nasal mucosa either by: i) enabling the encapsulation and delivery of high API payloads in only a few actuations, or even a single actuation, of a delivery device (such as a DPI) or (ii) maximizing the fine particle fraction of emitted doses of the pharmaceutical composition through modulation of the aerodynamic performance of the composite active particles. These dosing efficiencies result from the creation of composite active particles having a high tapped density (>0.4 g / cm3) with appropriate particles sizes for lung (Dv90 < 5 gm) or nasal (Dv90 > 10 gm) delivery that are surprisingly not highly cohesive and surprisingly have high dispersibility and excellent aerodynamic performance.

[0038] The pharmaceutical composition of the present invention is comprised of composite active particles comprising BTG and at least one API. BTG is the major whey protein from cow’s milk and other animal milks that can be isolated according to known methods and used in the present invention, p-lactoglobulin from synthetic or plant-based sources may also be used in the present invention. BTG extracted from milk and synthetic or plant-based BTG are commercially available, generally at a purity of >90% purity. High purity BTG is also described in e.g., W02021 / 110983A1.

[0039] In one aspect of the invention, there is provided a pharmaceutical composition wherein the BTG comprises from 1% to 99.9% by weight of the composite active particles. In a preferred aspect of the invention, the at least one API comprises from 20% to 99.5% of the composite active particles by weight. In a more preferred aspect of the invention, the at least one API comprises from 30% to 90% of the composite active particles by weight. In an optimal aspect of the invention, the at least one API comprises from 40% to 80% of the composite active particles by weight.

[0040] The identity of the at least one or more APIs in the pharmaceutical composition of the invention is not critical, and the present invention can be employed with a large variety of APIs (as shown by the present Examples). In a preferred aspect of the invention, the composite active particles comprise at least one API selected from the following therapeutic groups: antibiotics, antifungal agents, antiviral agents, antipsychotic agents, immunosuppressants, bronchodilators, anti-parkinsonian agents, anti-inflammatory or anti-cancer drugs. Examples of APIs useful in this invention include but are not limited to Streptomycin, Isoniazid, para-aminosalicylic acid, tobramycin, gentamycin, 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, baloxavir marboxil, ipratropium bromide, aclidinium bromide, tiotropium bromide, revefenacin, pirfenidone or nintedanib.

[0041] In another aspect of the invention, the API is an antiviral compound. For example, the API may be a broad-spectrum antiviral compound, such as remdesivir. The antiviral compound may, for example, be a protide compound (a prodrug of a nucleotide), which is able to diffuse into cells. In another aspect of the invention, the API is an antibiotic, such as an ansamycin antibiotic. Ansamycins are a family of bacterial secondary metabolites that show antimicrobial activity against many Gram-positive and some Gram-negative bacteria, and include various compounds, including streptovaricins and rifamycins. The ansamycin antibiotic compound may have an aromatic moiety, which can be a naphthalene ring or a naphthoquinone ring as in rifamycin and the naphthomycins. In other variations of the ansamycin antibiotic, the compound may have a benzene or a benzoquinone ring system, as in geldanamycin or ansamitocin.

[0042] In another aspect of the invention, the API is methacholine, or histamine, or nicotine, or salts thereof.

[0043] In another aspect of the invention, the API may be a vaccine, proteins, peptides, oligonucleotides, or nucleic acids.

[0044] In a preferred aspect of the invention, the composite active particles comprise API in an amorphous form. The composite active particles are, thus, preferably an amorphous solid dispersion (ASD) comprising an API and BTG. In an alternative aspect of the invention, the composite active particles may comprise API in crystalline form.

[0045] In one aspect of the invention, there is provided a pharmaceutical composition wherein the at least one API comprises from 0.1% to 99% by weight of the composite active particles. In a preferred aspect of the invention, the at least one API comprises from 0.5% to 80% of the composite active particles by weight. In a more preferred aspect of the invention, the at least one API comprises from 10% to 70% of the composite active particles by weight. In an optimal aspect of the invention, the at least one API comprises from 20% to 60% of the composite active particles by weight.

[0046] The composite active particles of the present invention have a tapped density of at least about 0.4 g / cm3. More preferably, the composite active particles of the present invention have a tapped density of at least about 0.5 g / cm3. These tapped density ranges are higher than that found in conventional spray-dried compositions, and are a particular advantage of the present invention for the purpose of packing high quantities of the composite particles into delivery devices or their capsules. Tapped density, as used herein, is measured in accordance with US Pharmacopeia (USP) <616>,(for example as set out in method 1 of May 2024 edition). Tapped density was determined by dividing the weight of the sample by its volume after compacting it in a container until no variations were observed in the volume upon compacting it further. The procedure involved placing a stopper in a container with a known weight of the material and compacting the content in the container by tapping mechanically 10, 500 and 1250 times, and reading each volume, VI 0, V500 and V1250 to consider a volume value for calculating density that does not further increase with additional taps. By standard procedure, additional tapping increments should be applied if the volume of the material does not stabilize as it continues to be compressed. An example of a container suitable for performing the tapping is a 250 mL graduated cylinder. Tapping may be performed, for example, at a height of 14 ± 2 mm at 300 ± 15 taps per minute.

[0047] In some examples, the composite active particles of the present invention have a tapped density of about 0.4 g / cm3to 0.8 g / cm3, optionally 0.4 g / cm3to 0.7 g / cm3, further optionally 0.4 g / cm3to 0.6 g / cm3, still further optionally 0.4 g / cm3to less than 0.6 g / cm3. In other examples, the composite active particles of the present invention have a tapped density of about 0.35 g / cm3to 0.8 g / cm3, optionally 0.35 g / cm3to 0.7 g / cm3, further optionally 0.35 g / cm3to 0.6 g / cm3, still further optionally 0.35 g / cm3to less than 0.6 g / cm3.

[0048] Based on the high tapped densities obtained with the composite active particles of the present invention, high fill weights in the cavities of delivery devices or the capsules used in such devices are obtainable. In one aspect, embodiments of the methods and compositions of the present invention increase the amount of composite active particles delivered from a small receptacle (e.g., a 0.1 mL blister) inhaler from about 1 mg to more than about 6, 7, 8, 9, or 10 mg. In another aspect, embodiments of methods and compositions of the present invention increase the total amount of composite active particles delivered from a medium-sized receptacle (e.g., a 0.27 mL size #3 capsule) inhaler from about 10 mg to more than about 50, 100, 110, 125, or 150 mg. In another aspect, embodiments of methods and compositions of the present invention increase the total amount of an API delivered from a larger-sized receptacle (e.g., 0.34 mL cavity of a Twin Max device) inhaler from about 50 mg to more than about 100, 150, 200, or 250 mg. In one aspect, embodiments of methods and compositions of the present invention can increase the amount of composite active particles that can be delivered, via a single inhalation / actuation, from a receptacle in a unit dose or single dose disposable dry powder inhaler to more than 100 mg.

[0049] To make the pharmaceutical compositions of the present invention, there first is provided a solvent system comprising (i) at least two solvents, wherein there is a first solvent that is comprised of one or more aqueous or organic solvents and there is a second solvent that is comprised of one or more organic solvents; (ii) at least one active pharmaceutical ingredient mixed in the solvent system; and (iii) BLG at least partially suspended in the solvent system.

[0050] The present invention utilizes the solvent system to induce the formation of BLG aggregates. By varying the combination of the first solvent and second solvent as well as the order of solvent mixing and BLG addition to the solvent system, the formation of BLG aggregates can be modulated. This modulation has been found to have a direct effect on the tapped density of the resulting composite active particles as well as their particle size distribution (PSD) and the fine particle fraction of emitted dose (FPF).Thus, the present invention enables the production of composite active particles with a tuneable aerodynamic performance and a high tapped density that provides for delivery of high drug payloads via inhalation or nasal delivery.

[0051] In one preferred aspect of the invention, the preparation of the solvent system comprises first mixing BLG in a first solvent comprising one or more aqueous or organic solvents, followed by the addition of a second solvent comprising one or more organic solvents to the mixture of BLG in the first solvent. In this aspect of the invention, preferably, the first solvent is an aqueous solvent, most preferably water. The one or more APIs are added into the solvent system based on their solubility profile. For example, if an API is water soluble then it can be added to the first solvent at any time prior to the addition of the second solvent to the first solvent. By contrast, if an API is water insoluble, then it can be added directly to the second solvent prior to its mixing with the first solvent or it can be added after the first solvent and second solvent have been mixed. The sequence of mixing in this preferred aspect of the invention, where the first solvent is an aqueous solvent, allows for the formation of fine BLG aggregates at least partially suspended in the solvent system. Following the removal of the solvents, composite active particles with excellent aerodynamic performance, high tapped densities, and a PSD typically suitable for inhalation delivery to the lungs are obtained.

[0052] In another preferred aspect of the invention, the preparation of the solvent system comprises first mixing BLG in a second solvent comprising one or more organic solvents, followed by the addition of a first solvent comprising one or more aqueous or organic solvents to the mixture of BLG in the second solvent. In this aspect of the invention, preferably, the first solvent is an aqueous solvent, most preferably water. The one or more APIs is added into the solvent system based on their solubility profile. For example, if an API is water soluble then it can be added to the first solvent at any time prior to the addition of the first solvent to the second solvent. By contrast, if an API is water insoluble, then it can be added directly to the second solvent prior to the addition of the first solvent or it can be added after the first solvent and second solvent have been mixed. The sequence of mixing in this preferred aspect of the invention, where the first solvent is an aqueous solvent, allows for the formation of coarse BLG aggregates at least partially suspended in the solvent system. Following the removal of the solvents, composite active particles with excellent aerodynamic performance, high tapped densities, and a PSD in a range typically suitable for nasal delivery are obtained.

[0053] To attain a finer particle size and enhance the fine particle fraction of the emitted dose of the composite active particles, in a preferred aspect of the present invention, the first solvent (one or more aqueous or organic solvents) is 10-70% by weight of the total combined weight of the first solvent and second solvent (one or more organic solvents) present in the solvent system. Alternatively, in another preferred aspect of the present invention, the first solvent is 20% by weight or above or more preferably 30% by weight or above of the total combined weight of the first solvent and second solvent present in the solvent system.

[0054] To attain a coarse particle size and enhance the deposition of the composite active particles in nasal delivery applications, in a preferred aspect of the present invention, BLG is firstly dispersed in the second solvent (one or more organic solvents) at 30-95% by weight of the total combined weight of first solvent and second solvent present in the solvent system. The second solvent (one or more aqueous or organic solvents) is then subsequently added.

[0055] In a preferred aspect of the invention, the second solvent comprising one or more organic solvents is selected from one or more of the following: methylene chloride, acetone, ethanol, methanol, tetrahydrofuran (THF), methyl ethyl ketone (MEK), acetonitrile, a polyethylene glycol, an organosulfur compound, or dimethyl sulfoxide (DMSO). In a preferred aspect of the invention, the first solvent comprising one or more aqueous or organic solvents is an aqueous solvent selected from one or more of the following: water, aqueous buffers, salt solutions, and water with any water-soluble excipient. In another aspect of the invention, when the first solvent is an organic solvent it is selected from one or more of the following: methylene chloride, acetone, ethanol, methanol, tetrahydrofuran (THF), methyl ethyl ketone (MEK), acetonitrile, a polyethylene glycol, an organosulfur compound, or dimethyl sulfoxide (DMSO). The solvent system of the present invention is not limited to a single first solvent and a single second solvent, but instead the solvent system can be comprised of binary, ternary or quaternary solvent systems.

[0056] The pharmaceutical composition of the invention may comprise, consist, or consist essentially of the composite active particles of the invention described herein. The pharmaceutical composition of the invention may, if desired, also comprise further components in addition to the composite active particles of API and the BLG, which may depend upon the API being used. Thus, the invention also provides a pharmaceutical composition as described herein wherein the pharmaceutical composition further comprises one or more of the following: glass formers, force control agents, stabilizers and / or solubilityenabling excipients such as lactose, mannitol, trehalose, magnesium stearate.

[0057] In another aspect of the invention, formation of the solvent system may comprise adding one or more additional excipients to the solvent system, which may depend on the APIs being used. For example, one or more of the following excipients may be added to the solvent system, and, thus, be included in the resulting composite active particles that are formed after solvent removal: glass formers, force control agents, stabilizers and / or solubility enabling excipients such as: lactose, mannitol, trehalose, magnesium stearate, dipalmitoylphosphatidylcholine (DPPC), cholesterol, phosphatidylcholine, l,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG), dipalmitoylphosphatidylglycerol (DPPG), Distearoylphosphatidylcholine (DSPC), F-leucine, trileucine, or other hydrophobic amino acids. Amino acids may comprise leucine, tryptophan, alanine, valine, isoleucine, trileucine, dileucine, methionine, phenylalanine, proline or a mixture of two or more thereof. An organic, physiologically acceptable, sterically demanding acid may also be added to the solvent system as a strategy to control BFG aggregation and be part of the resulting composite active particles that are formed after solvent removal. Such an acid may be selected from among ascorbic acid, a fruit or culinary acid and a mono-, di- or trivalent carboxylic acid. Additionally, other excipients may be used to at least partially control the formation of BFG aggregates in the solvent system.

[0058] In a further preferred aspect of the invention, in the method as disclosed herein, the particle size distribution of the composite active particles is controlled to enable inhalation delivery, including for deep lung delivery. Accordingly, the composite active particles of the present invention, as disclosed herein, have a Dv90 by laser diffraction of 10 pm or less. In a preferred aspect, the composite active particles have a Dv90 by laser diffraction of 5 pm or less. With these preferred values of Dv90, the composite active particles of the present invention provide for a suitable fine particle fraction of the emitted dose (FPF) of the pharmaceutical composition of from 15 to 90%. Preferably, the FPF of the pharmaceutical composition is 50% or more, more preferably greater than 60%. In one preferred aspect, the FPF of the pharmaceutical composition may be 80% or more.

[0059] In a further preferred aspect of the invention, in the method as disclosed herein, the particle size distribution of the composite active particles is controlled to enable nasal delivery Accordingly, the composite active particles of the present invention, as disclosed herein, have a Dv90 by laser diffraction of greater than 10 pm. With these preferred values of Dv90, the composite active particles of the present invention provide for a suitable fine particle fraction of the emitted dose (FPF) of the pharmaceutical composition of from 15 to 50%. Preferably, the FPF of the pharmaceutical composition is 30% or less, more preferably less than 20%, more preferably less than 15%.

[0060] Cascade impaction methods, such as the gravimetric Fast Screening Impactor (FSI) and the Next Generation Impactor (NGI), were used to determine key parameters of aerosolization of the composite active particles and may also be used to determine the same for the compositions comprising the particles, i.e. fine particle dose (FPD) and fine particle fraction (FPF), filled into size #3 capsules or the cavities of a TwinMax device (Hovione FarmaCiencia SA, Lisbon, Portugal). Capsules were actuated with a standard high resistance 2-pin inhaler device RS01 (Plastiape Spa, Osnago, Italy). Depending on the type of device, the volume of air around 4 L was aspirated from the RS01 or TwinMax inhalers at a flow rate that corresponded to a pressure drop of 4 kPa. This flow rate was set around 65 L / min for the RS01 inhalers and around 38 L / min for the TwinMax inhalers. The gravimetric FSI was equipped with a USP Induction Port and Pre- separator (with 65L / min insert) with an FSI filter. The NGI was equipped with USP Induction Port and Pre-separator (USP Apparatus 5). The emitted dose (ED) of each gravimetric FSI run was determined from the difference in weight before and after actuating the device. The FPD of each gravimetric FSI run was determined from the weighed mass of composite active particles recovered from the FSI filter. The fine particle fraction for each gravimetric FSI run was calculated from the FPD and ED as follows: FPF(%)=100 x(FPD) / (ED). When using the NGI, FPD and FPF were calculated with the CITDAS software (Copley) after determining with liquid chromatography the amount of API that was recovered from each of the NGI after actuation. In the Examples, NGI was used with the BLG: fluticasone furoate compositions and gravimetric FSI was used for the other pharmaceutical compositions / composite active particles produced in the examples of this invention: BLG: tobramycin compositions and 100 % BLG (placebo).

[0061] Other suitable methods may also be used to determine the aerodynamic performance of the composite active particles and the compositions comprising them, such as those described in US Pharmacopeia (USP) (e.g., May 2024 edition), <601 > Inhalation And Nasal Drug Products: Aerosols, Sprays, And Powders — Performance Quality Tests, USP < 1063 > Good Cascade Impactor Practices and USP <1064>Presentation Of Aerodynamic Particle Size Distribution (APSD) Measurement Data For Orally Inhaled Products.

[0062] As used herein, the particle size distribution (PSD) of the composite active particles are determined by laser diffraction with a Sympatec HELOS laser diffraction instrument (type BR or equivalent) using R1 or R2 lenses.

[0063] In a preferred aspect of the present invention, spray drying is used to remove the solvents from the solvent system to produce composite active particles that comprise BLG and at least one API, wherein the composite active particles have a tapped density of at least about 0.4 g / cm3. The general process of preparing spray-dried composite active particles is well known and described in the literature and can be employed to make the presently disclosed pharmaceutical compositions. Figure 1 illustrates the spray-drying set up used for producing composite active particles. A variety of atomization methods can be used, depending on the equipment chosen, for example two- or three-fluid nozzles, pressure, ultrasonic or rotary nozzles. The preferential atomization gas flow in terms of liters per hour can be adjusted to the equipment in use and any suitable atomization gas flow can be used. Typically, for a small-scale unit, 150 to 300 milliliters per hour is preferred. On an industrial scale a different gas flow may be used. Any suitable drying temperature can be used, ranging from about 30°C to about 220°C. The inlet temperature may be adjusted to attain the desired outlet temperature. Any suitable flow rate of the feedstock solvent system can be used. The outlet temperature, atomization flow rate, solvent system concentration and solvent system flow rate, among other parameters, can be combined and adjusted to obtain a composite active particle with suitable quality. The spray dried composite active particles obtained are typically amorphous and are 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 technique is, in general, below 25 pm and above 1 pm of medium particle size distribution, leading to composite active particles with high flowability and dispersibility. In particular, in view of the particle sizes produced, the composite active particles produced by spray drying are in the form of a powder.

[0064] As will be understood, if desired, after the solvent removal step, preferably by spray drying, a further secondary drying step may be performed to remove residual solvent. Such a secondary drying step may be carried out using any suitable method, as will be understood by those skilled in the art.

[0065] After the solvent removal and collection of the composite active particles, at least one pharmaceutically acceptable excipient may optionally be added to the composite active particles.

[0066] The method may further comprise filling the pharmaceutical composition comprising or consisting of the composite active particles into a container. The container may be a blister cavity, a capsule suitable for use with an inhaler device, or a reservoir suitable for use with an inhaler device. In one example, the container may be a size #3 capsule. The container may comprise 50 to 200 mg of the pharmaceutical composition, preferably 50 to 150 mg of the pharmaceutical composition.

[0067] Other container sizes, capsule sizes, or blister sizes can be used in the invention to contain different amounts of the pharmaceutical composition.

[0068] The inhaler device may be any device suitable for pulmonary or nasal application of the pharmaceutical composition. In particular, the device may be a dry powder inhaler.

[0069] In summary, the method of producing a pharmaceutical composition comprising composite active particles according to the present invention as described herein may typically comprise the two following steps: a. manufacturing composite active particles using an appropriate solvent system in accordance with the various embodiments of the present invention described herein, wherein the manufactured composite active particles comprise BTG and at least one active pharmaceutical ingredient and wherein the composite active particles have a tapped density of at least about 0.4 g / cm3; b. optionally, filling the pharmaceutical composition comprising the composite active particles into suitable containers, such as blister cavities, capsules, or reservoirs for use in inhaler devices for pulmonary or nasal applications.

[0070] The pharmaceutical composition of the invention may be used in a method of administering the pharmaceutical composition to a subject in need thereof. In particular, the pharmaceutical composition may be used to administer an effective dose of the API to the subject. The pharmaceutical composition may be administered from the inhaler device and / or container described above. In preferred examples, the pharmaceutical composition is nasally administered or administered via inhalation. Examples

[0071] Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following Examples. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be considered to, limit its scope in any way.

[0072] Example 1 - Critical quality attributes of composite particles of BLG placebo.

[0073] To understand the critical quality attributes of spray-dried particles obtained from modulation of the BLG aggregation profiles in accordance with the methods of the present invention, several BLG placebo compositions were prepared, in accordance with the methods of the present invention, in different solvent systems, as shown in Table 1. BLG was Lacprodan® (Aria Eoods Ingredients) extracted from bovine whey and comprising BLG at more than 90% of the total protein. To prepare the solvent system, BLG was added first in either organic solvent (Trials 1 to 7) or water (Trials 8 to 15). Organic solvents used in this example were dichloromethane (DCM, also referred to in the art as methylene chloride), methanol, and acetone. In Trials 1 to 7, BLG was first mixed in organic solvent, which formed coarse aggregates of BLG, and then water was subsequently added to the mixture of organic solvent and BLG to yield a suspension of coarse aggregates of BLG in the solvent system. Whereas, in Trials 8 to 15, BLG was first mixed into water, and then organic solvent was subsequently added to the water and BLG mixture to form a suspension of fine aggregates of BLG in the solvent system.

[0074] As illustrated in Figure 1, a lab scale spray dryer (Btichi, model B-290), equipped with a two-fluid nozzle, was used to atomize and dry each of the previously described solvent systems. Co-current nitrogen was used to promote drying after atomization (F_drying). The spray drying unit was operated in open cycle mode (i.e., without recirculation of the drying gas). Before feeding the solvent system into the spray dryer, the spray drying unit was stabilized with nitrogen to ensure stable inlet (T_in) and outlet temperatures (T_out). After stabilization, the solvent system was fed to the nozzle by means of a peristaltic pump and atomized at the tip of the nozzle. The droplets were then dried in the spray drying chamber by co-current nitrogen. The stream containing the composite particles was directed into a cyclone and collected at the bottom. The composite particles were then post-dried to meet ICH residual solvent standards. The main operating parameters during the spray-drying process for each trial are summarized in Table 1.

[0075] Table 1 - Summary of the solvent systems and associated spray-drying parameters for Trials 1- 15.

[0076] The composite particles of BLG placebo obtained in Trials 1-15 after spray drying was an amorphous solid. Several tests confirm its amorphous form, such as x-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). The appearance of the atomized material was characterized by means of scanning electron microscopy (SEM). The particle size distribution of the composite particles of BLG placebo was determined using a Sympatec HELOS laser diffraction instrument.

[0077] The tapped densities for Trials 5 and 12 were tested and found to be 0.56 and 0.44 g / cm3, respectively. Based on observation and working with the composite particles of the other Trials in this Example, it is understood that the tapped densities of the other Trials in this example also were above 0.4 mg / cm3. The composite particles of BLG placebo were filled into HPMC size 3 capsules at a fill weight of 30 mg to stress the powder dispersibility dynamics of a DPI. Capsule filling was performed using a gravimetric Auger feeder and no clogging was observed. The aerodynamic particle size distribution (aPSD) properties were measured using the FSI impaction method with a single capsule actuation in a high resistance RS01 DPI device (65 L / min). All trials evidenced excellent emitted doses ranging from 83.7% to 99.9%, and surprisingly, FPF ranges greater than 60% for particle size distributions having a Dv90 less than 5 pm. Figures 2A to 2C and Table 2 demonstrate that all solvent systems resulted in an excellent emitted dose with the DPI device. These data also show how different solvent systems can modulate both the fine particle dose or fine particle fraction of the composite particles of BLG placebo in a controlled and unexpectedly tunable fashion. Dissolving BLG in water of both Acetone / Water and Ethanol / Water based systems generated suspensions of fine aggregates of BLG up to 80% of organic solvent fraction (w / w) with a FPF ranging from 66.8% to 90.6% (fit for deep lung delivery), after which the increasing organic content led to coarser suspensions with poorer fine particle fractions - FPF ranging from 28.0% to 41.1%. In acetone / water solvent systems, where BLG was added to the organic fraction, a coarse suspension was generated with unfolded BLG that seemed to have gelled, significantly increasing the particle size distribution of the composite particles of BLG placebo and decreasing fine particle fraction and showcasing a promising deposition profile for upper respiratory tract or nasal delivery. With a fully organic and significantly less polar DCM / Methanol solvent system, an immediate suspension of BLG was generated which yielded a coarser PSD and poorer FPF (18-19%).

[0078] Figures 3A to 3C showcases the correlation between the particle size distribution obtained after spray drying and the fine particle dose depending on the solvent system used. The observed solvent-related data clusters suggest how different extents of BLG aggregation and solvent entrapment led to increasing total residual solvents content after spray drying pointing to the fink between organic controlled BLG aggregation and droplet drying kinetics. The cluster of trials where BLG was added to acetone presented the highest residual solvent content after spray drying (4.4-5.1% w / w), being also the cluster with the coarser particle size and poorer FPF. The cluster where BLG was added to the aqueous fraction of the same solvent system, inverted the protein aggregation kinetics showcasing the finest aggregates of suspended BLG, highest FPD and lowest residual solvents content after spray drying at equivalent atomization and drying conditions (1.1 -2.6% w / w). With such tunable aerodynamic performance, delivery performance in vivo may therefore be fine-tuned to the target therapeutic profile of choice, regardless of it being a deep lung delivery with optimally high FPF, a higher respiratory tract deposition target with lower FPF, or even an immediate deposition profile within the nasal cavity towards nasal delivery.

[0079] Table 2 - Particle size, capsule fill weight and aerodynamic performance.

[0080] Example 2 - Spray-dried composite active particles having high tapped density.

[0081] Composite active particles were prepared according to the present invention using a solvent system comprising different combinations of water and organic solvents (acetone or ethanol), as shown in Table 3. To prepare the solvent system, BLG was added first in either water (Trials 16, 18, and 19) or organic solvent (Trials 17 and 20). In Trials 16, 18, and 19, BLG was first dissolved in water and then the organic solvent was subsequently added to the solution of water and BLG to promote controlled aggregation of the BLG in the solvent system. Whereas, in Trials 17 and 20, BLG was first mixed into the organic solvent, which formed coarse aggregates of BLG, and then water was subsequently added to form a coarser suspension of BLG in the solvent system, which was subsequently stabilized under mild stirring. In Trials 16, 18, and 19, the API (fluticasone furoate) was dissolved in the solvent system after the addition of the organic solvent to the mixture of water and BLG; in Trials 17 and 20, the API was added to the mixture of organic solvent and BLG prior to the addition of water.

[0082] The solvent system of each Trial was then spray dried using the same lab-scale spray dryer system described in Example 1 and shown in Figure 1. The main operating parameters during the spray-drying process for each Trial are summarized in Table 3. All trials were subsequently efficiently post-dried to meet ICH residual solvent standards.

[0083] Table 3 - Summary of the solvent systems and associated spray-drying parameters for Trials 16- 20.

[0084] All composite particles obtained in Trials 16-20 were amorphous solids, as confirmed by x-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The appearance of the composite active particles also was characterized by means of scanning electron microscopy (SEM).

[0085] As shown in Table 4, the density profiles and particle size distributions of the five Trials were determined in accordance with the methods previously described. The dispersibility and aerodynamic performance of the composite active particles was also assessed. The composite active particles were filled into HPMC size 3 capsules at a fill weight of 30 mg for the placebo trials (Trials 16 and 17) to stress the powder dispersibility dynamics of a DPI and 12.5 mg for the BLG:fluticasone furoate trials (Trials 18-20) to mimic the target dose of the Relvar Ellipta commercial benchmark. Capsule filling was performed using a gravimetric Auger feeder and no clogging was observed. The aerodynamic particle size distribution (aPSD) properties were determined using the NGI impaction method with a single capsule actuation in a high resistance RS01 DPI device (65 L / min). Surprisingly, with equivalent atomization and drying conditions, a high and tunable range of tapped densities were attained (> 0.4 g / cm3) for the various Trials, which depended on the solvent system used, including the identity of the organic solvent and the order of mixing of BLG when forming the solvent system (added first to either the water or organic solvent fraction). As shown in Figure 4, despite the surprisingly high-density profiles of the composite active particles, which exceed the tapped densities of the typical dry powder used in inhalation systems, excellent aerodynamic performance and fine particle fraction were observed for both the placebo trials and BLG:fluticasone furoate trials.

[0086] Table 4 - Summary of solid-state characteristics and aerodynamic performance data of Trials 16- 20.

[0087] Example 3 - High dose delivery of composite active particles.

[0088] Composite active particles were prepared according to the present invention by first dissolving BLG in water, subsequently adding the organic solvent (ethanol) to the solution of BLG and water, and then dissolving the API (tobramycin) in the BLG-water-ethanol mixture to form a solvent system. The solvent system was then spray dried using the same lab-scale spray dryer system described in Example 1 and shown in Figure 1. The main operating parameters during the spray-drying process for this Trial 21 are summarized in Table 5.

[0089] Table 5 - Summary of the solvent system and associated spray-drying parameters for Trial 21.

[0090] The composite active particles obtained were an amorphous solid. Based on observation and experience with Trial 19 of Example 2, which also utilized a 70% / 30% Ethan ol / Water solvent combination with BLG first mixed into the water fraction, it is understood that the tapped density of the composite active particles for this Trial 21 also are above 0.4 mg / cm3.

[0091] The composite active particles were filled into hydroxypropyl methylcellulose (HPMC) size3 capsules using either a gravimetric Auger feeder or a manual dosator at increasing compression profiles to ascertain if the excellent dispersibility characteristics of BTG could enable high dose delivery of the tobramycin API. The target fill weight was in the range of 30 to 106.6 mg of the composite active particles (15 to 53.3 mg of tobramycin) and the aPSD properties were measured using an FSI impaction method with a single capsule actuation in a high resistance RS01 DPI device (65 T / min). As demonstrated in Figures 5A to 5C, regardless of the tested fill weight, it was surprisingly found that an excellent emitted dose (> 90%) and a high aerodynamic performance was attained, reaching an FPF between 43 and 68% and resulting in the current configuration of a delivery of composite active particles of up to 56 mg to the deep lung in a single HPMC #3 capsule actuation. The estimated fine particle dose of tobramycin relates to the measured fine particle dose of the composite active particles with a 50% drug load of API. Comparing such profiles with a commercial Tobi Podhaler benchmark where 48.5 mg of powder are filled in size #2 capsules (0.37 mF - packing density 131 mg / mL), filling up to 106mg of the composite active particles of the present invention in smaller size 3 capsules (0.27 mL volume - 392.6 mg / mL packing density) enables filling capsules at a 3 fold increase with maintenance of excellent aerodynamic performance, thus enabling higher dose delivery and reducing clinical burden when several actuations are needed to deliver a therapeutic dose.

[0092] Example 4 - High amorphization potential of composite active particles using BLG as the sole excipient and complemented with additional excipients.

[0093] To understand the potential for BLG to stabilize amorphous active pharmaceutical ingredients, compositions were prepared according to the present invention with Fluticasone Furoate (a hydrophobic API) and Tobramycin (a hydrophilic API) as shown in Table 6. Briefly, BLG was first mixed in water with subsequent addition of organic fraction or directly mixed in the organic fraction, after which the API was mixed into the biphasic solvent system. Trehalose supplementation was performed in the final biphasic solvent system.

[0094] The solvent system was then spray dried using the same lab-scale spray dryer system described in Example 1 and shown in Figure 1. The main operating parameters during the spraydrying process for Trials 22-28 of this Example are summarized in Table 6.

[0095] Table 6 - Summary of the solvent systems and associated spray-drying parameters for Trials 22- 28.

[0096] XRPD results (Figures 6A to 6G) show maintenance of the API amorphous state when BLG was added to fluticasone furoate or tobramycin in the respective biphasic solvent systems used to feed the spray dryer. With fluticasone furoate, a low dose of 1.6% and a high dose of 75% for final spray dried product were characterized. Low dose of fluticasone furoate spray dried after mixing it with equal parts of trehalose and leucine resulted in a crystalline product (Trial 22), while an amorphous state was observed when a product with the same API concentration was produced with BLG (Trial 23). This result suggested superiority of BLG as an excipient in spray drying for the development of inhalable pharmaceutical amorphous solid dispersions. Reversion of fluticasone furoate towards a crystalline state was observed in a spray dried powder produced with BLG and 75% of the fluticasone furoate API (Trial 24). However, adding trehalose at a concentration of 10% induced maintenance of the amorphous state of the spray dried product at this high load of fluticasone furoate API (Trial 25), showing that BLG can also be complemented with other pharmaceutical excipients for the development of high drug load pharmaceutical amorphous solid dispersions. Tobramycin was tested for being a model API for high drug load formulations and was spray dried with BLG at 25%, 50% and 75% (Trials 26-28, respectively). Maintenance of the API amorphous state after spray drying was observed at all the tested concentrations of tobramycin.

[0097] Example 5 - Composite active particles tunable for nasal delivery.

[0098] To assess if composite active particles could be produced with promising deposition profiles for nasal delivery, a composition was prepared according to the present invention. BLG and fluticasone furoate were mixed in acetone, and the water fraction was subsequently added to form the solvent system. The solvent system was then spray dried using the same lab-scale spray dryer system described in Example 1 and shown in Figure 1. The main operating parameters during the spray-drying process for this Trial 29 are summarized in Table 7.

[0099] Table 7 - Summary of the solvent system and associated spray-drying parameters for Trial 29.

[0100] The composite active particles obtained using the method of this invention is an amorphous solid. Size #3 capsules were filled with 12.5 mg of a composition containing 1.6% of fluticasone furoate and the performance of their actuation in the context of nasal delivery was evaluated with an Alberta Idealized Nasal Inlet (AINI) equipped with a Fast-screening impactor (FSI) and following standard procedures for operating these apparatuses. One capsule was actuated with a reference device for nasal delivery and fluticasone furoate was recovered in methanol after each actuation from the capsule, device, AINI regions (vestibule, olfactory region (OR), turbinates, nasopharynx), and FSI regions (pre-separator (PS), and filter). The experiment was performed in triplicate. The amount of fluticasone furoate recovered from each stage was quantified with high performance liquid chromatography and results are presented in Figures 7 A to 7D. Most of the API is deposited in the nasal regions comprising the vestibule, olfactory region and turbinates, and amounts recovered from the device / capsule were in the same range as what was recovered from the nasopharynx and FSI pre-separator. Overall, these results show the potential of BEG as an excipient to be used in nasal drug products produced as described via spray drying after mixing it in biphasic solvent systems.

[0101] Example 6 -Composite active particles comprising BLG with differentAPIs for high dose delivery.

[0102] Besides fluticasone furoate and tobramycin, high drug load formulations were prepared according to the present invention with vancomycin and levodopa to demonstrate that BEG can encapsulate APIs with a wide variety of chemical attributes into high drug load inhalable dry powder formulations with the inventive attributes described herein: i) tapped density > 0.4g / mE; ii) particle size distribution (Dv90<10pm) adequate for inhalation. A meth anokwater biphasic solvent system was selected for both APIs based on their solubility profile targeting a 70:30 w / w ratio and 2% total solids concentration. For preparing the spray drying feed stock solution, BEG was first dissolved in water, then vancomycin was added to this aqueous mixture before addition of the organic fraction. Regarding Eevodopa, after the dissolution of BEG in the aqueous fraction, the organic solvent was added after which the API was dissolved in the biphasic solvent mixture. A lab scale spray dryer (Biichi, model B-290 - Figure 1), equipped with a two fluid nozzle, was used to atomize, and dry the solutions. Droplet drying after atomization was done with co-current nitrogen. The spray drying unit was operated in open cycle mode (i.e., without recirculation of the drying gas).

[0103] Before feeding the solution to the nozzle, the spray drying unit was stabilized with nitrogen to assure stable inlet (T_in) and outlet temperatures (T_out). After stabilization, the solution was fed to the nozzle by means of a peristaltic pump and atomized at the tip of the nozzle. The droplets were dried in the spray drying chamber by a concurrent nitrogen drying stream. 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 8.

[0104] Table 8 - Summary of the main operating conditions for developing Vancomycin and Fevodopa formulations at 0, 25, 50 and 75% (w / w) drug load.

[0105] The spray dried dispersion (SDD) was subsequently efficiently post-dried to meet ICH residual solvent standards. The density and particle size distribution of the obtained SDDs were assayed. Dry powder resultant from these trials using the method of this invention was then filled into size #3 capsules at 48 mg fill weight with a gravimetric Auger feeder. Capsules were used to determine the aerodynamic particle size distribution (aPSD) of the dry powder resulting from each with a gravimetric fast screening impaction method via a single capsule actuation in a high resistance DPI device (65L / min). A summary of the obtained SDD characterization results, capsule filling and corresponding aerodynamic performance is detailed in Table 9 and Figures 8A to 8F.

[0106] Regardless of the tested API, highly dense particles (Figure 8A - 0.37<TD<0.65g / cm3) were obtained throughout the entire range of encapsulated drug-loads, yielding fine particle size distributions aligned with inhalation delivery (Figure 8B - 1.2<Dv50< 2.2pm).

[0107] Regarding capsule filling, compared with commercial benchmarks, the commercial Inbrija platform for levodopa refers to a target dose of 42 mg of levodopa per 00 capsule, corresponding to 46.7 mg / ml API packing density in Inbrija vs 131 ,5mg / mL API packing density in BFG filled size 3 HPMC capsules. This result reflects a 2.8 fold increase of current invention example applied to levodopa relative to commercial benchmark. The commercial vancomycin Aerovanc platform reported values of up to 16mg of target dose (59.3 mg / ml API packing density) in Size 3 capsules for Aerovanc vs 130.7mg / mF API packing density in BFG filled size 3 HPMC capsules, implying a 2.2 fold increase relative to benchmark. Remarkably, despite the significant increase in packing density, pertaining to aerosolization performance, excellent dispersibility characteristics were observed with emitted doses ranging from 72 to 100% (Figure 8C) for all the trials with up to 35.6mg of levodopa and 35.2mg of vancomycin emitted from the capsules. All high drug load trials evidenced appropriate aerosolization properties for deep lung delivery, with levodopa presenting fine particle fractions ranging between 24 to 44% and Vancomycin ranging between 50 to 79% (Figure 8D). Aligned with prior embodiments, a robust correlation was observed for each API between fine particle fraction and particle size distribution (Figure 8F) evidencing how particle engineering can be fine-tuned towards specific target deposition profiles.

[0108] Table 9 - Particle Size Distribution by Laser Diffraction (Sympatec), capsule filling fill weight and aerodynamic performance by Fast Screening Impactor (FSI - Copley)

[0109] These results emphasize how BLG can efficiently encapsulate and deliver high payloads of a wide variety of APIs with distinct chemical attributes ranging from hydrophilic to hydrophobic, small to large molecules, poor to good glass formers with acceptable to challenging crystallization kinetics, reinforcing its potential as a universal solution for high-dose inhalation therapies. The successful integration of APIs with challenging solubility profiles and varying molecular weights into high- density composite particles exemplifies the invention’s capacity to meet clinical needs while enhancing patient compliance and therapeutic efficacy.

[0110] These results emphasize how BLG can efficiently encapsulate and deliver high payloads of a wide variety of APIs with distinct chemical attributes ranging from hydrophilic to hydrophobic, small to large molecules, poor to good glass formers with acceptable to challenging crystallization kinetics, reinforcing its potential as a universal solution for high-dose inhalation therapies. The successful integration of APIs with challenging solubility profiles and varying molecular weights into high- density composite particles exemplifies the invention’s capacity to meet clinical needs while enhancing patient compliance and therapeutic efficacy. List of Items of the Invention

[0111] In view of the above, the present specification in particular relates to the following Items:

[0112] 1. A pharmaceutical composition comprising composite active particles, wherein the composite active particles comprise [Tlactoglobulin and at least one active pharmaceutical ingredient and wherein the composite active particles have a tapped density of at least about 0.35 g / cm3.

[0113] 2. The pharmaceutical composition according to Item 1, wherein the composite active particles have a tapped density of at least about 0.4 g / cm3.

[0114] 3. The pharmaceutical composition according to Item 2, wherein the composite active particles have a tapped density of at least about 0.5 g / cm3.

[0115] 4. The pharmaceutical composition according to Item 1, wherein the composite active particles have a tapped density of about 0.35 g / cm3to about 0.8 g / cm3.

[0116] 5. The pharmaceutical composition according to Item 4, wherein the composite active particles have a tapped density of about 0.35 g / cm3to about 0.7 g / cm3.

[0117] 6. The pharmaceutical composition according to Item 5, wherein the composite active particles have a tapped density of about 0.35 g / cm3to about 0.6 g / cm3, preferable about 0.35 g / cm3to less than 0.6 g / cm3.

[0118] 7. The pharmaceutical composition according to any of Items 3 to 6, wherein the composite active particles have a tapped density of at least about 0.4 g / cm3.

[0119] 8. The pharmaceutical composition according to any preceding Item, wherein the particle size of the composite active particles is suitable for inhalation delivery or for nasal delivery.

[0120] 9. The pharmaceutical composition according to any preceding Item, wherein the fine particle fraction of an emitted dose of the pharmaceutical composition is from 15 to 90%.

[0121] 10. The pharmaceutical composition according to any preceding Item, wherein the fine particle fraction of an emitted dose of the pharmaceutical composition is greater than about 30%.

[0122] 11 The pharmaceutical composition according to any preceding Item, wherein the fine particle fraction of an emitted dose of the pharmaceutical composition is greater than about 50%.

[0123] 12. The pharmaceutical composition according to any preceding Item, wherein the fine particle fraction of an emitted dose of the pharmaceutical composition is greater than about 80%.

[0124] 13. The pharmaceutical composition according to any of Items 1 to 8, wherein the fine particle fraction of an emitted dose of the pharmaceutical composition is from 15 to 50%.

[0125] 14. The pharmaceutical composition according to any of Items 1 to 8 or 13, wherein the fme particle fraction of an emitted dose of the pharmaceutical composition is less than about 30%.

[0126] 15. The pharmaceutical composition according any preceding Item, wherein the composite active particles have a Dv90 of about 10 pm or less. 16. The pharmaceutical composition according to Item 15, wherein the composite active particles have a Dv90 of about 5 pm or less.

[0127] 17. The pharmaceutical composition according to any of Items 1 to 14, wherein the composite active particles have a Dv90 greater than about 10 pm.

[0128] 18. The pharmaceutical composition according to any preceding Item, wherein the composite active particles further comprise at least one pharmaceutically acceptable excipient.

[0129] 19. The pharmaceutical composition according to Item 18, wherein the at least one pharmaceutically acceptable excipient is selected from one or more of the following: glass formers, force control agents, stabilizers, and / or solubility enabling excipients, such as: lactose, mannitol, trehalose, magnesium stearate, dipalmitoylphosphatidylcholine (DPPC), cholesterol, phosphatidylcholine, 1 ,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG), dipalmitoylphosphatidylglycerol (DPPG), Distearoylphosphatidylcholine (DSPC), T-leucine, or tri-leucine.

[0130] 20. The pharmaceutical composition according to any preceding Item, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0131] 21. The pharmaceutical composition according to Item 20, wherein the at least one pharmaceutically acceptable excipient is one or more of the following: glass formers, force control agents, stabilizers and / or solubility enabling excipients such as: lactose, mannitol, trehalose, magnesium stearate.

[0132] 22. The pharmaceutical composition according to any preceding Item, wherein the at least one active pharmaceutical ingredient comprises from about 0.1% to about 99% of the composite active particles by weight.

[0133] 23. The pharmaceutical composition according to any preceding Item, wherein the at least one active pharmaceutical ingredient comprises from about 20% to about 60% of the composite active particles by weight.

[0134] 24. The pharmaceutical composition according to any preceding Item, wherein the 0- lactoglobulin comprises from about 1% to about 99.9% of the composite active particles by weight.

[0135] 25. The pharmaceutical composition according to any preceding Item, wherein the 0- lactoglobulin comprises from about 40% to about 80% of the composite active particles by weight.

[0136] 26. The pharmaceutical composition according to any preceding Item, wherein the composite active particles are an amorphous solid dispersion.

[0137] 27. The pharmaceutical composition according to any preceding Item, wherein the composition is in the form of a powder.

[0138] 28. A method of making a pharmaceutical composition comprising: a. providing a solvent system comprising: (i) at least two solvents, wherein there is a first solvent that is comprised of one or more aqueous or organic solvents and there is a second solvent that is comprised of one or more organic solvents; (ii) at least one active pharmaceutical ingredient mixed in the solvent system; and (iii) p-lactoglobulin at least partially suspended in the solvent system; b. removing the solvents from the solvent system to produce composite active particles that comprise p-lactoglobulin and at least one active pharmaceutical ingredient, wherein the composite active particles have a tapped density of at least about 0.35 g / cm3; c. collecting the composite active particles.

[0139] 29. The method of making a pharmaceutical composition according to Item 28 wherein the composite active particles have a tapped density of at least about 0.4 g / cm3.

[0140] 30. The method of making a pharmaceutical composition according to Item 29 wherein the composite active particles have a tapped density of at least about 0.5 g / cm3.

[0141] 31. The method of making a pharmaceutical composition according to any of Items 28-30, wherein the solvents are removed by spray drying.

[0142] 32. The method of making a pharmaceutical composition according to any of Items 28-31, wherein the first solvent comprises water.

[0143] 33. The method of making a pharmaceutical composition according to any of Items 28-32, wherein the second solvent is selected from one or more of the following: methylene chloride, acetone, ethanol, methanol, tetrahydrofiiran (THF), methyl ethyl ketone (MEK), acetonitrile, a polyethylene glycol, an organosulfur compound, or dimethyl sulfoxide (DMSO).

[0144] 34. The method of making a pharmaceutical composition according to any of Items 28-33, wherein the method further comprises adding at least one pharmaceutically acceptable excipient to the solvent system.

[0145] 35. The method of making a pharmaceutical composition according to any of Items 28-34, wherein the method further comprises adding at least one pharmaceutically acceptable excipient to the collected composite active particles.

[0146] 36. The method of making a pharmaceutical composition according to any of Items 28 to 35, wherein in (a) the p-lactoglobulin at least partially suspended in the solvent system comprises aggregates of p-lactoglobulin.

[0147] 37. A method of making a pharmaceutical composition comprising: a. providing a first solvent that is comprised of one or more aqueous or organic solvents; b. mixing p-lactoglobulin in the first solvent to form a mixture of -lactoglobulin and first solvent; c. providing a second solvent that is comprised of one or more organic solvents; d. mixing the second solvent with the mixture of -lactoglobulin and first solvent to form a solvent system comprising the first solvent, the second solvent, and aggregates of P-lactoglobulin at least partially suspended in the solvent system; e. adding at least one active pharmaceutical ingredient into the solvent system by adding the at least one active pharmaceutical ingredient into one of the following: the first solvent; the mixture of 0-lactoglobulin and first solvent; the second solvent; or the mixture of first solvent, second solvent, and 0-lactoglobulin; f. removing the solvents from the solvent system to produce composite active particles that comprise 0-lactoglobulin and at least one active pharmaceutical ingredient, wherein the composite active particles have a tapped density of at least about 0.35 g / cm3; g. collecting the composite active particles.

[0148] 38. The method of making a pharmaceutical composition according to Item 37, wherein the composite active particles have a tapped density of at least about 0.4 g / cm3.

[0149] 39. The method of making a pharmaceutical composition according to Item 37 or Item 38, wherein the composite active particles have a tapped density of at least about 0.5 g / cm3.

[0150] 40. The method of making a pharmaceutical composition according to any of Items 37-39, wherein the solvents are removed by spray drying.

[0151] 41. The method of making a pharmaceutical composition according to any of Items 37-40, wherein the first solvent comprises water, and preferably wherein in (b) the mixture of 0- lactoglobulin and the first solvent is 0-lactoglobulin dissolved in water.

[0152] 42. The method of making a pharmaceutical composition according to any of Items 37-41, wherein the second solvent is selected from one or more of the following: methylene chloride, acetone, ethanol, methanol, tetrahydrofiiran (THF), methyl ethyl ketone (MEK), acetonitrile, a polyethylene glycol, an organosulfur compound, or dimethyl sulfoxide (DMSO).

[0153] 43. The method of making a pharmaceutical composition according to any of Items 37-42, wherein in (d) the mixing of the mixture of 0-lactoglobulin and the first solvent with the second solvent forms the aggregates of 0-lactoglobulin at least partially suspended in the solvent system.

[0154] 44. The method of making a pharmaceutical composition according to any of Items 37-43, wherein the method further comprises adding at least one pharmaceutically acceptable excipient to the solvent system.

[0155] 45. The method of making a pharmaceutical composition according to any of Items 37-44, wherein the method further comprises adding at least one pharmaceutically acceptable excipient to the collected composite active particles.

[0156] 46. The method of making a pharmaceutical composition according to any of Items 37-45, wherein the first solvent is 10-70 % by weight of the total combined weight of the first solvent and the second solvent.

[0157] 47. The method of making a pharmaceutical composition according to any of Items 37 to 46, wherein the first solvent is 20% by weight or more, preferably 30% by weight or more, of the total combined weight of the first solvent and the second solvent.

[0158] 48. A method of making a pharmaceutical composition comprising: a. providing a first solvent that is comprised of one or more aqueous or organic solvents; b. providing a second solvent that is comprised of one or more organic solvents; c. mixing 0-lactoglobulin in the second solvent to form a mixture of 0-lactoglobulin and second solvent; d. mixing the first solvent with the mixture of 0-lactoglobulin and second solvent to form a solvent system comprising the first solvent, second solvent, and aggregates of 0- lactoglobulin at least partially suspended in the solvent system; e. adding at least one active pharmaceutical ingredient into the solvent system by adding the at least one active pharmaceutical ingredient into one of the following: the first solvent; the second solvent; the mixture of 0-lactoglobulin and second solvent; or the mixture of first solvent, second solvent, and 0-lactoglobulin; f. removing the solvents from the solvent system to produce composite active particles that comprise 0-lactoglobulin and at least one active pharmaceutical ingredient, wherein the composite active particles have a tapped density of at least about 0.35 g / cm3; g. collecting the composite active particles.

[0159] 49. The method of making a pharmaceutical composition according to Item 48, wherein the composite active particles have a tapped density of at least about 0.4 g / cm3.

[0160] 50. The method of making a pharmaceutical composition according to Item 48 or Item 49, wherein the composite active particles have a tapped density of at least about 0.5 g / cm3.

[0161] 51. The method of making a pharmaceutical composition according to any of Items 48-50, wherein the solvents are removed by spray drying.

[0162] 52. The method of making a pharmaceutical composition according to any of Items 48-51, wherein the first solvent comprises water.

[0163] 53. The method of making a pharmaceutical composition according to any of Items 48-52, wherein the second solvent is selected from one or more of the following: methylene chloride, acetone, ethanol, methanol, tetrahydrofiiran (THF), methyl ethyl ketone (MEK), acetonitrile, a polyethylene glycol, an organosulfur compound, or dimethyl sulfoxide (DMSO).

[0164] 54. The method of making a pharmaceutical composition according to any of Items 48-53, wherein in (c) the mixing of 0-lactoglobulin in the second solvent forms the aggregates of 0- lactoglobulin at least partially suspended in the second solvent.

[0165] 55. The method of making a pharmaceutical composition according to any of Items 48-54, wherein the method further comprises adding at least one pharmaceutically acceptable excipient to the solvent system.

[0166] 56. The method of making a pharmaceutical composition according to any of Items 48-55, wherein the method further comprises adding at least one pharmaceutically acceptable excipient to the collected composite active particles. 57. The method of making a pharmaceutical composition according to any of Items 48-56, wherein the second solvent is 30-95 % by weight of the total combined weight of the first solvent and the second solvent.

[0167] 58. The method of making a pharmaceutical composition according to any of Items 28-57, wherein the pharmaceutical composition is according to any of Items 1 to 27.

[0168] 59. The method of making a pharmaceutical composition according to any of Items 28-58, further comprising filling the pharmaceutical composition comprising the composite active particles into a container, optionally wherein the container is a blister cavity, a capsule for use with an inhaler device for pulmonary or nasal applications, or a reservoir for use with an inhaler device for pulmonary or nasal applications, further optionally wherein the container is a size #3 capsule.

[0169] 60. A pharmaceutical composition prepared by the method of any of Items 28-58.

[0170] 61. A container comprising the pharmaceutical composition of any of Items 1 to 27, optionally wherein the container is a blister cavity, a capsule for use with an inhaler device for pulmonary or nasal applications, or a reservoir for use with an inhaler device for pulmonary or nasal applications, optionally wherein the container is a size #3 capsule.

[0171] 62. An inhaler device suitable for pulmonary or nasal applications, comprising the pharmaceutical composition of any of Items 1 to 24, or the container of Item 55, optionally wherein the inhaler device is a dry powder inhaler.

[0172] 63. A pharmaceutical composition according to any of Items 1 to 27 or 60 for use in medicine.

[0173] 64. A method of administering the pharmaceutical composition of any of Items 1 to 27 or 60, wherein the pharmaceutical composition is administered via inhalation.

[0174] 65. The method of administering the pharmaceutical composition of Item 64, wherein more than about 50 mg of the pharmaceutical composition is filled into a size #3 capsule.

[0175] 66. The method of administering the pharmaceutical composition of Item 64 or Item 65, wherein more than about 100 mg of the pharmaceutical composition is filled into a size #3 capsule.

[0176] 67. The method of administering the pharmaceutical composition according to any of Items 64-66, wherein the fine particle fraction of an emitted dose of the pharmaceutical composition is greater than about 30%.

[0177] 68. The method of administering the pharmaceutical composition of Item 67, wherein the fine particle fraction of an emitted dose of the pharmaceutical composition is greater than about 50%.

[0178] 69. The method of administering the pharmaceutical composition of Item 68, wherein the fine particle fraction of an emitted dose of the pharmaceutical composition is greater than about 80%.

[0179] 70. A method of administering the pharmaceutical composition of any of Items 1 to 27 or 60, wherein the pharmaceutical composition is nasally administered. 71. The method of administering the pharmaceutical composition of Item 70, wherein more than about 50 mg of the pharmaceutical composition is filled into a size #3 capsule.

[0180] 72. The method of administering the pharmaceutical composition of Item 70 or Item 71, wherein more than about 100 mg of the pharmaceutical composition is filled into a size #3 capsule.

[0181] 73. The method of administering the pharmaceutical composition of any of Items 70-72, wherein the fine particle fraction of an emitted dose of the pharmaceutical composition is less than about 30%.

[0182] 74. The pharmaceutical composition according to any of Items 1 to 27 or 60 for use in delivering or administering the API to a subject.

[0183] 75. The pharmaceutical composition for use according to Item 74, wherein the use comprises administering the pharmaceutical composition via inhalation.

[0184] 76. The pharmaceutical composition for use according to Item 74, wherein the use comprises administering the pharmaceutical composition nasally.

[0185] 77. Use of the pharmaceutical composition of any of Items 1 to 27 or 60 for the manufacture of a medicament for use in delivering or administering the API to subject.

[0186] 78. Use according to Item 77, wherein the pharmaceutical composition is to be administered via inhalation.

[0187] 79. Use according to Item 77, wherein the pharmaceutical composition is to be administered via nasal administration.

Claims

Claims1. A pharmaceutical composition comprising composite active particles, wherein the composite active particles comprise p-lactoglobulin and at least one active pharmaceutical ingredient and wherein the composite active particles have a tapped density of at least about 0.35 g / cm3.

2. A pharmaceutical composition according to Claim 1, wherein the composite active particles have a tapped density of at least about 0.4 g / cm3or at least about 0.5 g / cm3.

3. A pharmaceutical composition according to Claim 1 or Claim 2, wherein the fme particle fraction of an emitted dose of the pharmaceutical composition is greater than about 30%.

4. A pharmaceutical composition according to Claim 3, wherein the fme particle fraction of an emitted dose of the pharmaceutical composition is greater than about 50%.

5. A pharmaceutical composition according to Claim 4, wherein the fme particle fraction of an emitted dose of the pharmaceutical composition is greater than about 80%.

6. A pharmaceutical composition according to Claim 1 or Claim 2, wherein the fme particle fraction of an emitted dose of the pharmaceutical composition is less than about 30%.

7. A pharmaceutical composition according to Claim 1 or Claim 2, wherein the composite active particles have a Dv90 of about 10 pm or less.

8. A pharmaceutical composition according to Claim 7, wherein the composite active particles have a Dv90 of about 5 pm or less.

9. A pharmaceutical composition according to Claim 1 or Claim 2, wherein the composite active particles have a Dv90 greater than about 10 pm.

10. A pharmaceutical composition according to any preceding claim, wherein the composite active particles further comprise at least one pharmaceutically acceptable excipient.

11. A pharmaceutical composition according to Claim 10, wherein the at least one pharmaceutically acceptable excipient is selected from one or more of the following: glass formers, force control agents, stabilizers, and / or solubility enabling excipients, such as: lactose, mannitol, trehalose, magnesium stearate, dipalmitoylphosphatidylcholine (DPPC), cholesterol, phosphatidylcholine, l,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG), dipalmitoylphosphatidylglycerol (DPPG), Distearoylphosphatidylcholine (DSPC), L- leucine, or tri-leucine.

12. A pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

13. A pharmaceutical composition according to Claim 12, wherein the at least one pharmaceutically acceptable excipient is one or more of the following: glass formers, force control agents, stabilizers and / or solubility enabling excipients such as: lactose, mannitol, trehalose, magnesium stearate.

14. A pharmaceutical composition according to any preceding claim, wherein the at least one active pharmaceutical ingredient comprises from about 0.1% to about 99% of the composite active particles by weight.

15. A pharmaceutical composition according to any preceding claim, wherein the at least one active pharmaceutical ingredient comprises from about 20% to about 60% of the composite active particles by weight.

16. A pharmaceutical composition according to any preceding claim, wherein the 0- lactoglobulin comprises from about 1% to about 99.9% of the composite active particles by weight.

17. A pharmaceutical composition according to any preceding claim, wherein the 0- lactoglobulin comprises from about 40% to about 80% of the composite active particles by weight.

18. A method of making a pharmaceutical composition comprising: a. providing a solvent system comprising: (i) at least two solvents, wherein there is a first solvent that is comprised of one or more aqueous or organic solvents and there is a second solvent that is comprised of one or more organic solvents; (ii) at least one active pharmaceutical ingredient mixed in the solvent system; and (iii) 04actoglobulin at least partially suspended in the solvent system; b. removing the solvents from the solvent system to produce composite active particles that comprise 04actoglobulin and at least one active pharmaceutical ingredient, wherein the composite active particles have a tapped density of at least about 0.35 g / cm3; c. collecting the composite active particles.

19. A method of making a pharmaceutical composition according to Claim 18, wherein the composite active particles have a tapped density of at least about 0.4 g / cm3or at least about 0.5 g / cm3.

20. A method of making a pharmaceutical composition according to Claim 18 or Claim 19, wherein the solvents are removed by spray drying.

21. A method of making a pharmaceutical composition according to any of Claims 18-20, wherein the first solvent comprises water.

22. A method of making a pharmaceutical composition according to any of Claims 18-21, wherein the second solvent is selected from one or more of the following: methylene chloride, acetone, ethanol, methanol, tetrahydrofuran (THF), methyl ethyl ketone (MEK), acetonitrile, a polyethylene glycol, an organosulfur compound, or dimethyl sulfoxide (DMSO).

23. A method of making a pharmaceutical composition according to any of Claims 18-22, wherein the method further comprises adding at least one pharmaceutically acceptable excipient to the solvent system.

24. A method of making a pharmaceutical composition according to any of Claims 18-23, wherein the method further comprises adding at least one pharmaceutically acceptable excipient to the collected composite active particles.

25. A method of making a pharmaceutical composition comprising: a. providing a first solvent that is comprised of one or more aqueous or organic solvents; b. mixing p-lactoglobulin in the first solvent to form a mixture of p-lactoglobulin and first solvent; c. providing a second solvent that is comprised of one or more organic solvents; d. mixing the second solvent with the mixture of p-lactoglobulin and first solvent to form a solvent system comprising the first solvent, the second solvent, and aggregates of p-lactoglobulin at least partially suspended in the solvent system; e. adding at least one active pharmaceutical ingredient into the solvent system by adding the at least one active pharmaceutical ingredient into one of the following: the first solvent; the mixture of p-lactoglobulin and first solvent; the second solvent; or the mixture of first solvent, second solvent, and -lactoglobulin; f. removing the solvents from the solvent system to produce composite active particles that comprise p-lactoglobulin and at least one active pharmaceutical ingredient, wherein the composite active particles have a tapped density of at least about 0.35 g / cm3; g. collecting the composite active particles.

26. A method of making a pharmaceutical composition according to Claim 25, wherein the composite active particles have a tapped density of at least about 0.4 g / cm3or at least about 0.5 g / cm3.

27. A method of making a pharmaceutical composition according to Claim 25 or Claim 26, wherein the solvents are removed by spray drying.

28. A method of making a pharmaceutical composition according to any of Claims 25-27, wherein the first solvent comprises water.

29. A method of making a pharmaceutical composition according to any of Claims 25-28, wherein the second solvent is selected from one or more of the following: methylene chloride, acetone, ethanol, methanol, tetrahydrofuran (THF), methyl ethyl ketone (MEK), acetonitrile, a polyethylene glycol, an organosulfur compound, or dimethyl sulfoxide (DMSO).

30. A method of making a pharmaceutical composition according to any of Claims 25-29, wherein the method further comprises adding at least one pharmaceutically acceptable excipient to the solvent system.

31. A method of making a pharmaceutical composition according to any of Claims 25-30, wherein the method further comprises adding at least one pharmaceutically acceptable excipient to the collected composite active particles.

32. A method of making a pharmaceutical composition comprising: a. providing a first solvent that is comprised of one or more aqueous or organic solvents; b. providing a second solvent that is comprised of one or more organic solvents; c. mixing p-lactoglobulin in the second solvent to form a mixture of p-lactoglobulin and second solvent; d. mixing the first solvent with the mixture of p-lactoglobulin and second solvent to form a solvent system comprising the first solvent, second solvent, and aggregates of P-lactoglobulin at least partially suspended in the solvent system; e. adding at least one active pharmaceutical ingredient into the solvent system by adding the at least one active pharmaceutical ingredient into one of the following: the first solvent; the second solvent; the mixture of p-lactoglobulin and second solvent; or the mixture of first solvent, second solvent, and -lactoglobulin; f. removing the solvents from the solvent system to produce composite active particles that comprise p-lactoglobulin and at least one active pharmaceutical ingredient, wherein the composite active particles have a tapped density of at least about 0.35 g / cm3; g. collecting the composite active particles.

33. A method of making a pharmaceutical composition according to Claim 32, wherein the composite active particles have a tapped density of at least about 0.4 g / cm3or at least about 0.5 g / cm3.

34. A method of making a pharmaceutical composition according to Claim 32 or Claim 33 wherein the solvents are removed by spray drying.

35. A method of making a pharmaceutical composition according to any of Claims 32-34, wherein the first solvent comprises water.

36. A method of making a pharmaceutical composition according to any of Claims 32-35, wherein the second solvent is selected from one or more of the following: methylene chloride, acetone, ethanol, methanol, tetrahydrofuran (THF), methyl ethyl ketone (MEK), acetonitrile, a polyethylene glycol, an organosulfur compound, or dimethyl sulfoxide (DMSO).

37. A method of making a pharmaceutical composition according to any of Claims 32-36, wherein the method further comprises adding at least one pharmaceutically acceptable excipient to the solvent system.

38. A method of making a pharmaceutical composition according to any of Claims 32-37, wherein the method further comprises adding at least one pharmaceutically acceptable excipient to the collected composite active particles.

39. A method of administering the pharmaceutical composition of Claims 7 or 8, wherein the pharmaceutical composition is administered via inhalation.

40. A method of administering the pharmaceutical composition of Claim 39, wherein more than about 50 mg of the pharmaceutical composition is filled into a size #3 capsule.

41. A method of administering the pharmaceutical composition of Claim 40, wherein more than about 100 mg of the pharmaceutical composition is filled into a size #3 capsule.

42. A method of administering the pharmaceutical composition of Claims 39-41, wherein the fine particle fraction of an emitted dose of the pharmaceutical composition is greater than about 30%.

43. A method of administering the pharmaceutical composition of Claim 42, wherein the fine particle fraction of an emitted dose of the pharmaceutical composition is greater than about 50%.

44. A method of administering the pharmaceutical composition of Claim 43, wherein the fine particle fraction of an emitted dose of the pharmaceutical composition is greater than about 80%.

45. A method of administering the pharmaceutical composition of Claim 9, wherein the pharmaceutical composition is nasally administered.

46. A method of administering the pharmaceutical composition of Claim 45, wherein more than about 50 mg of the pharmaceutical composition is filled into a size #3 capsule.

47. A method of administering the pharmaceutical composition of Claim 46, wherein more than about 100 mg of the pharmaceutical composition is filled into a size #3 capsule.

48. A method of administering the pharmaceutical composition of Claims 45-47, wherein the fine particle fraction of an emitted dose of the pharmaceutical composition is less than about 30%.

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