KR20140032404A - Compositions, methods & systems for respiratory delivery of two or more active agents - Google Patents

Abstract

Provided are compositions, methods and systems for pulmonary or nasal delivery of two or more active agents via a quantitative aspirator. In one embodiment, the composition comprises suspension medium, activator particles and suspension particles, wherein the activator particles and suspension particles form a co-suspension in the suspension medium.

Description

COMPOSITIONS, METHODS & SYSTEMS FOR RESPIRATORY DELIVERY OF TWO OR MORE ACTIVE AGENTS}

The present disclosure generally relates to compositions, methods, and systems for respiratory delivery of two or more active agents. In certain embodiments, the present disclosure relates to compositions, methods, and systems for respiratory delivery of two or more active agents, wherein one or more of the active agents is a long-acting muscarin antagonist (“LAMA”), long-acting β ₂ adrenergic agonists (“LABA”), and corticosteroid actives.

Targeted drug delivery methods that deliver active agents at the site of action are often desired. For example, targeted delivery of an active agent may reduce undesirable side effects, reduce dosage requirements, and reduce treatment costs. In the context of respiratory delivery, aspirators are well known devices for the administration of active agents to the respiratory tract of a subject, and several different aspirator systems are now commercially available. Three conventional aspirator systems include dry powder aspirators, nebulizers and quantitative aspirators (MDI).

MDI can be used for pharmaceutical delivery in solubilized form or as a suspension. Typically, MDI uses a relatively high vapor pressure propellant to eject aerosolized droplets containing the active agent into the airways when the MDI is activated. Dry powder aspirators generally rely on the patient's respiratory effort to introduce restrictions in the form of dry powder into the airways. Nebulizer forms, on the other hand, form pharmaceutical aerosols that are aspirated by energizing a liquid solution or suspension.

MDI is an active delivery device that uses the pressure generated by the propellant. Typically, chlorofluorocarbons (CFCs) have been used as propellants in MDI systems because of their low toxicity, desirable vapor pressure and suitability for stable suspension formulation. However, traditional CFC propellants have been understood to have a negative environmental impact, leading to the development of alternative propellants, such as perfluorinated compounds (PFC) and hydrofluoroalkanes (HFA), which are considered more environmentally friendly.

The active agent delivered by the suspension MDI is typically provided as fine particles dispersed in a propellant or a combination of two or more propellants (ie, a propellant “system”). For fine particle formation, the active agent is usually micronized. Fine particles of the active agent suspended in the propellant or propellant system tend to aggregate or clump rapidly. This is especially true for active agents present in micronized form. Aggregation or coagulation of the microparticles may then complicate the delivery of the active agent. For example, agglomeration or coagulation can lead to mechanical disturbances, such as those that can be caused by the closing of the valve orifice of the aerosol container. Unwanted agglomeration or coagulation of drug particles can also lead to rapid precipitation or creaming of the drug particles, and such behavior can result in inadequate drug delivery, which is particularly problematic for very strong, low dose constraints. Can be. Another problem associated with the suspension MDI formulations relates to the crystal growth of the drug during storage, which in turn provides a decrease over time of the aerosol properties and delivery dose uniformity of the MDI. More recently, a solution approach as disclosed in US Pat. No. 6,964,759 has been proposed for MDI formulations comprising choline inhibitors (anticholinergics).

One approach to improving aerosol performance in dry powder aspirators incorporates fine particle carrier particles such as lactose. The use of such microexcipients has not been studied on a large scale for MDI. Young et al., "The influence of micronized particulates on the aerosolization properties of pressurized metered dose inhalers"; Aerosol Science 40, pgs. 324-337 (2009) suggest that the use of such fine particle carriers in MDI results in a decrease in aerosol performance.

In traditional CFC systems, when the active agent present in the MDI formulation is suspended in the propellant or propellant system, the surfactant is often applied to the surface coating of the active agent to minimize or prevent the problem of aggregation and maintain a substantially uniform dispersion. Is used. The use of surfactants in that manner is sometimes referred to as "stabilization" of the suspension. However, many surfactants that are soluble in CFC systems and effective are not effective in HFA and PFC propellant systems because the surfactants exhibit different solubility characteristics in non-CFC propellants.

1 is a graph showing delivery dose uniformity of co-suspension formulations containing glycopyrrolate and formoterol fumarate prepared according to the present disclosure.
FIG. 2 is a graph showing the delivered dose ratio of the co-suspension formulation of FIG. 1.
3 is a graph showing delivery dose uniformity of a second co-suspension formulation prepared according to the present disclosure.
FIG. 4 is a graph showing the delivered dose ratio of the second co-suspension formulation of FIG. 3.
FIG. 5 is a graph showing delivery dose uniformity of glycopyrrolate and formoterol fumarate in co-suspension formulations prepared according to the present disclosure upon storage under the different conditions indicated.
FIG. 6 is a graph showing particle size distribution of exemplary co-suspension formulations prepared according to the present disclosure upon storage under the different conditions indicated. FIG.
7 provides a graph illustrating particle size distribution achieved by an example co-suspension comprising a combination of glycopyrrolate and formoterol fumarate upon storage at the indicated conditions.
8 is achieved by an exemplary co-suspension comprising a combination of glycopyrrolate and formoterol fumarate as compared to particle size distribution achieved by a formulation comprising glycopyrrolate or formoterol fumarate alone. A graph describing the particle size distribution to be provided.
FIG. 9 is a graph showing the serum glycopyrrolate and formoterol concentration levels over time achieved after delivery of an exemplary co-suspension comprising glycopyrrolate and formoterol fumarate prepared according to the present disclosure. Serum concentration time profiles of glycopyrrolate and formoterol fumarate delivered from an example combination formulation are compared to those achieved by compositions containing and delivering glycopyrrolate or formoterol fumarate alone.
10 is a form achieved by a double co-suspension prepared according to the present disclosure comprising microcrystalline formoterol fumarate and glycopyrrolate activator particles compared to a co-suspension containing only crystalline formoterol fumarate. It is a graph showing the moterol particle size distribution.
FIG. 11 includes microcrystalline glycopyrrolate activator particles and microcrystalline formoterol fumarate activator particles or spray dried formoterol fumarate having two different particle size distributions (representing “fine” and “crude”). , A graph showing the glycopyrrolate particle size distribution achieved by the double co-suspension prepared according to the present specification.
FIG. 12 is prepared according to the present disclosure comprising microcrystalline formoterol fumarate and microcrystalline glycopyrrolate activator particles compared to containing microcrystalline glycopyrrolate activator particles and spray dried formoterol fumarate particles. Is a graph showing the formoterol fumarate particle size distribution achieved by the second double co-suspension.
FIG. 13 is a graph showing delivery dose uniformity of glycopyrrolate and formoterol fumarate in an exemplary double co-suspension formulation prepared according to the present disclosure.
14 depicts delivery dose uniformity of each active agent included in an exemplary triple co-suspension composition comprising microcrystalline glycopyrrolate, formoterol fumarate and mometasone furoate active agent particles.
FIG. 15 shows a formoterol fumarate aerodynamic particle size distribution achieved in a triple co-suspension prepared according to the present disclosure comprising microcrystalline glycopyrrolate, formoterol fumarate and mometasone furoate activator particles; It is a graph comparing what was achieved in double co-suspensions including pyrrolate and formoterol fumarate.
FIG. 16 shows glycopyrrolate aerodynamic particle size distribution achieved in a triple co-suspension prepared according to the present disclosure comprising microcrystalline glycopyrrolate, formoterol fumarate and mometasone furoate activator particles. It is a graph showing a comparison between what was achieved in double co-suspensions including late and formoterol fumarate.
FIG. 17 shows glycopyrrolate achieved by triple co-suspensions prepared according to the present disclosure comprising formoterol fumarate and mometasone furoate microcrystalline activator particles, in addition to glycopyrrolate or tiotropium bromide activator particles. And tiotropium bromide aerodynamic particle size distribution.
FIG. 18 is a graph showing glycopyrrolate aerodynamic size distribution achieved by two dual and one single component co-suspensions prepared according to the present disclosure. Dose proportionality between two dual co-suspensions as well as equivalents between dual and single component co-suspensions.
FIG. 19 is a graph showing formoterol fumarate aerodynamic size distribution achieved by two double and two single component co-suspensions prepared according to the present disclosure. Dose proportionality between two dual and two single component co-suspensions as well as equivalents between dual and single component co-suspensions.
FIG. 20 is a graph depicting delivery dose uniformity of very low formoterol fumarate single component co-suspensions prepared according to the present disclosure.
FIG. 21 shows a combination co-suspension composition described herein, compared to two different single active agent delivery (one delivering only glycofylate-GP36 and the second delivering only tiotropium bromide-Spiriva). GP / FF 72 / 9.6 and GP / FF 36 / 9.6) is a graph showing the cumulative response over time on day 1 of the administration of two treatments. This composition was administered to the patient as part of the clinical study described in Example 12. Specifically, the graph shows FEV ₁ of ≥ 12%. The percentage of patients achieving improvement and the time at which the percentage is achieved are illustrated.
The treatment 22 to 24 is on a variety of research composition is administered to a patient as part of a clinical study described in Example 12, 7 days (Day 7) FEV ₁ AUC ₀ at _- describes the average change from the ₁₂ reference line Provide a graph. Treatment with the combinatorial co-suspension compositions (GP / FF 72 / 9.6 and GP / FF 36 / 9.6) described herein may be carried out using an active composition that delivers a placebo and a variety of different single active agents (one solely glycopyrrolate-GP 36). The second delivers only tiotropium bromide -Spiriva and the third delivers only formoterol fumarate-FF 7.2, FF 9.6 and Foradil).
25 is a FEV ₁ AUC ₀ on Day 7 for Example 12. Clinical Study each active composition administered to a patient as part of the study described in _a graph which illustrates the _12. FEV ₁ AUC ₀ provided by each active than placebo in the study compositions _- The improvement of ₁₂ appears.
26 is a GP 36, FF 9.6, the FEV ₁ is a graph illustrating the differences between AUC _{0 -12} achieved by a GP / FF 36 / 9.6 treatment on Day 7 compared to Spiriva and Foradil active comparator. As can be easily recognized with reference to 26, GP / FF 36 / 9.6 treatment FEV ₁ AUC _{0 -} provided a significantly better improvement of _12.
FIG. 27 is a graph showing peak FEV ₁ at treatment day 1 (day 1) and day 7 achieved by various study compositions administered to patients as part of the clinical study described in Example 12. Vertex FEV ₁ shown Shows the peak change in FEV ₁ from baseline provided by each of the active study compositions relative to placebo on the study days indicated.
28 Apex FEV ₁ achieved by GP / FF 36 / 9.6 treatment on Days 1 and 7 compared to Spiriva and Foradil Activity Comparators A graph illustrating the difference between. As can be readily appreciated with reference to FIG. 28, GP / FF 36 / 9.6 treatment provided a significantly better improvement of peak FEV ₁ compared to the active comparator.
29 is a graph illustrating the improvement in Morning Trough FEV ₁ achieved by various study compositions administered to a patient as part of the clinical study described in Example 12. The graph shows the improvement in Morning Trough FEV ₁ values provided by each of the active study compositions over placebo.
FIG. 30 is a clinical study described in Example 12, provided by two treatments with different single active comparators and the combination co-suspension compositions (GP / FF 72 / 9.6 and GP / FF 36 / 9.6) described herein relative to each other. Is a graph showing the difference between the increase in pre-administration FEV ₁ at day 7. As can be readily appreciated with reference to FIG. 30, GP / FF 72 / 9.6 and GP / FF 36 / 9.6 treatment provided a significantly better improvement of pre-administered FEV ₁ compared to a single active comparator, but compared to each other. Did not make a significant difference.
FIG. 31 is a placebo provided by two treatments with the Spiriva activity comparator composition and the combination co-suspension composition (GP / FF 72 / 9.6 and GP / FF 36 / 9.6) administered as part of the clinical study described in Example 12. Graphs illustrating the first and seventh day peaks of the relative inspiratory capacity (IC) and the seventh day pre-dose improvement are provided.
FIG. 32 provides a graph illustrating the consistent patient response achieved in the clinical studies described in Example 12, regardless of chronic obstructive pulmonary disease experienced by the patient.

details

The present disclosure provides compositions, methods and systems for respiratory delivery of two or more active agents. Specifically, in certain embodiments, the present disclosure includes pharmaceutical compositions, systems, and methods for respiratory delivery of two or more active agents via MDI, and in certain embodiments one or more of the active agents is a long-acting muscarinic antagonist ("LAMA"), long-acting β ₂ adrenergic agonists ("LABA"), and corticosteroid actives. The compositions described herein can be formulated for pulmonary or nasal delivery via MDI. The methods described herein include methods of stabilizing a formulation comprising two or more active agents for respiratory delivery, as well as methods of pulmonary delivery of two or more active agents for treating a lung disease or disorder via MDI. Also described herein are MDI systems for the delivery of two or more active agents, as well as methods of making such systems.

Formulation of pharmaceutical compositions incorporating two or more active agents is often challenging due to changes in the formulation resulting from unpredictable or unexpected interactions between the active agents or the incorporation of multiple active agents. This interaction is generally known as the "combination effect" and with respect to suspension formulations delivered from MDI, the combination effect is derived from the similarity between a formulation comprising a single active agent and a formulation comprising a combination of two or more active agents. Departures may be evident in one or more of the following areas: aerosol and particle size distribution characteristics provided by the formulation; Delivery dose uniformity for one or more active agents; Deliverability or absorption of one or more active agents; Or dose proportionality observed with one or more active agents.

In certain embodiments, the co-suspension compositions described herein have no combinatorial effect associated with the combination formulation. For the purposes of the present specification, a composition is a comparable formulation wherein, in the selected active agent, the aerosol properties achieved by the combination formulation, the particle size distribution characteristics, and the delivery dose uniformity are the only active agent selected active agents. There is no combinatorial effect unless it deviates from what is achieved by. In some embodiments, the lack of a combinatorial effect is such that the plasma concentration over time for the target dose of the selected active agent delivered from the combination formulation is equal to that of the formulation in which the selected active agent is comparable (the active agent is the selected active agent). When delivered in a dosage, it is demonstrated for the selected active agent unless it deviates from the plasma concentration achieved over time.

As used herein, the phrase “do not deviate” means that, for a given variable, the performance achieved by the combination formulation is ± that of that achieved by a comparable formulation comprising only one of the active agents included in the combination formulation. Means 20%. In certain embodiments, the performance achieved by the combination formulation is no different than that achieved by a comparable formulation comprising only one of the active agents included in the combination. For example, a co-suspension comprising two or more active agents as described herein can be delivered over time with respect to each of the active agents above a given dose, aerosol properties, particle size distribution characteristics, delivery achieved by the combination co-suspension It is believed that no combination effect is seen when one or more of the dose uniformity, and the plasma concentration, is within ± 20% of that achieved by a comparable formulation comprising only a single active agent. In some embodiments, for each active agent at a given dose, one or more of the aerosol properties, particle size distribution characteristics, delivery dose uniformity, and plasma concentrations achieved over time by the combination co-suspension composition described herein. Within ± 15% of that achieved by a comparable formulation comprising only this single active agent. In another embodiment, for each active agent at a given dose, one of the aerosol properties over time, particle size distribution characteristics, delivery dose uniformity, and plasma concentration achieved by the combination co-suspension composition described herein The above is within ± 10% of that achieved by a comparable formulation comprising only a single active agent. In certain embodiments, with respect to each active agent in a given dosage, the combination co-suspension composition as described herein comprises only one of the active agents included in the combination in one or more of the following regions Does not differ from: aerosol properties of the formulation over time; Particle size distribution characteristics; Delivery dose uniformity; And plasma concentration.

Combinations of two or more active agents included in the compositions provided herein may, in some embodiments, provide advantages with respect to pharmaceutical formulations comprising only a single active agent. For example, if a combination of two or more active agents is delivered simultaneously, the therapeutically effective dose of both active agents may be relatively less than if any combination of active agents are delivered alone, thereby preventing possible side effects or Decrease. Combinations of two or more active agents can also achieve more rapid expression or longer therapeutic effect periods than can be achieved by delivering one of the combined active agents alone.

In certain embodiments, the methods described herein include methods of treating lung diseases or disorders that are susceptible to treatment by respiratory delivery of co-suspension compositions as described herein. For example, the compositions, methods and systems described herein can be used to treat inflammatory or obstructive pulmonary disease or condition. In certain embodiments, the compositions, methods, and systems described herein can be used to improve airway hyperresponsiveness as a result of asthma, chronic obstructive pulmonary disease (COPD), other drug therapy, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergy In response to disturbed breathing, dyspnea syndrome, pulmonary arterial hypertension, pulmonary vasoconstriction, and combination administration of, for example, LAMA, LABA, corticosteroids, or other active agents alone or as other therapies as described herein. It can be used to treat patients suffering from a disease or disorder selected from any other respiratory disease, condition, trait, genotype or phenotype that may be possible. In certain embodiments, the compositions, systems, and methods described herein can be used to treat pulmonary inflammation and occlusion associated with cystic fibrosis. As described herein, the terms "COPD" and "chronic obstructive pulmonary disease" refer to chronic obstructive pulmonary disease (COLD), chronic obstructive airway disease (COAD), chronic airflow restriction (CAL) and chronic obstructive respiratory disease ( CORD) and chronic bronchitis, bronchiectasis and emphysema. As used herein, the term "asthma" refers to intrinsic (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, severe asthma, asthma of bronchitis, exercise-induced asthma, occupation Asthma and asthma caused after bacterial infection. Asthma is also understood to include wheezy-infant syndrome.

When administered to a patient suffering from pulmonary disease, embodiments of the co-suspension compositions described herein provide one or more significant increases in measurement of lung function or dose as compared to compositions that deliver only a single active agent. In certain such embodiments, delivery of the co-suspension composition described herein, including two or more active agents, yields a significant increase in one or both of FEV ₁ and inspiratory capacity (IC) relative to compositions containing only a single active agent. .

It will be readily understood that the embodiments generally described herein are exemplary. The following detailed description of various embodiments is not intended to limit the present disclosure, but is merely representative of various embodiments. As such, the details cited herein may include independently patentable subject matter. Moreover, the steps or acts of the methods described in connection with the embodiments disclosed herein may be changed by one skilled in the art without departing from the scope of the present disclosure. In other words, unless a particular order of steps or actions is essential to the proper manipulation of an embodiment, the order of use of the specific steps or actions may be reversed.

I. Justice

Unless specifically defined otherwise, technical terms used herein have the general meaning understood in the art. The following terms are specifically defined for clarity.

The term “active agent” refers to any agent, drug, including therapeutic, pharmaceutical, pharmacological, diagnostic, cosmetic and prophylactic and immunomodulatory agents that can be used or administered to humans or animals for any purpose. Used to include compounds, compositions, or other materials. The term “active agent” can be used interchangeably with the terms “drug”, “drug”, “pharmaceutical”, “drug substance” or “therapeutic agent”. As used herein, “active agent” can also include natural or homeopathic products that are not generally considered therapeutic.

The terms "associate", "associate with" or "associate" mean interaction between a chemical entity, composition or structure in proximity to a surface, such as the surface of another chemical entity, composition or structure or Refers to relationship. Associations include, for example, adsorption, adhesion, covalent bonds, hydrogen bonds, ionic bonds and electrostatic attraction, Lifshitz-van der Waals interactions and polar interactions. The term "attach" or "attach" is a form of association and is used as a generic term for all forces of tendency for particles or agglomerates to attract to the surface. “Attach” also refers to the particles contacting each other, crosslinking and retaining, thereby substantially freeing visible separation between the particles due to the different buoyancy in the propellant under normal conditions. In one embodiment, particles that adhere to or bind to a surface are included in the term “attach”. Typical conditions may include storage at room temperature or under gravitational acceleration. As described herein, the activator particles can associate with the suspension particles to form a co-suspension, wherein the visible separation between the suspended particles and the activator particles due to the buoyancy difference in the propellant is substantially indicative of their coagulation. none.

"Suspension particles" refer to a substance or combination of substances that is acceptable for respiratory delivery and acts as a vehicle for the active particles. Suspension particles interact with the active agent particles to facilitate repeatable administration, delivery or transport of the active agent to a target site of delivery, ie, the respiratory tract. Suspended particles described herein may be dispersed in a suspension medium comprising a propellant or propellant system and configured according to any shape, size or surface feature suitable for achieving the desired suspension stability or active agent delivery performance. Exemplary suspension particles include particles that exhibit a particle size that promotes respiratory delivery of the active agent and have a physical arrangement suitable for the formulation and delivery of the stabilized suspensions described herein.

The term “co-suspension” refers to a suspension of two or more particles having different compositions in a suspension medium, wherein one particle associates at least partially with one or more of the other particle types. The association results in an observable change in one or more features of at least one of the individual particle types suspended in the suspension medium. Features that are modified by association include, for example, one or more rates of flocculation or coagulation, the rate and nature of separation, ie, settling or creaming, the density of the cream or settling layer, adhesion to the vessel wall, valve components, etc. One or more of the rate and level of dispersion in adhesion and shaking may be included.

Exemplary methods for assessing whether a co-suspension is present may include the following: A pycnometric density measured using one particle type pycnometer is greater than the propellant, and another particle type pycnometer is used. If the measured density is smaller than the propellant, visual observation of creaming or sedimentation behavior can be employed to determine the presence of the co-suspension. The term "density measured using a nasal bottle" refers to the density of the material constituting the particles, excluding the void space in the particles. In one embodiment, the materials may be formulated or transferred in clear vials, generally glass vials, for visual observation. After the initial shaking, the vial is left for a time sufficient for sedimentation or formation of a cream layer, typically 24 hours. If the settling or cream layer is observed as a completely or nearly uniform monolayer, then the co-suspension is present. The term “co-suspension” includes partial co-suspensions, where the majority of two or more particle types associate with each other, but separation of some (ie less than the majority) of two or more particle types can be observed.

Exemplary co-suspension tests can be performed at different propellant temperatures to highlight the sedimentation or creaming behavior of particle types with a density close to the propellant density at room temperature. If different particle types have the same separation properties, ie all settle or all cream, other characteristics of the suspension, such as the rate of aggregation or coagulation, the rate of separation, the density of the cream or sedimentation layer, adhesion to the vessel wall, valve components Adhesion to, and dispersion rate and level upon shaking can be measured and compared to each characteristic of similarly suspended individual particle types to determine the presence of co-suspension. Various analytical methods generally known to those skilled in the art can be employed for the characterization.

Nominal administration, in the context of a composition comprising or providing agglomerates, particles, droplets, etc., suitable for breathing, such as the compositions described herein, the term "fine particle dosage" or "FPD" is within a range suitable for breathing. It refers to the dose in the total mass or fraction of the dose or metered dose. Dosages within the range suitable for breathing are doses deposited in vitro at the stage of the cascade impactor, namely Next Generation Impactor, operated at a flow rate of 30 l / min. Is measured as the sum of the dose delivered from the third stage to the filter.

In the context of a composition comprising or providing a clot, particles, droplets, or the like suitable for breathing, such as the compositions described herein, the term "fine particle fraction" or "FPF" refers to a delivered dosage that is within a range suitable for breathing ( That is, the proportion of material to be delivered relative to the amount present in the actuator of the delivery device, such as MDI. The amount of material delivered within the appropriate range to breathe is the amount of material deposited in the inlet end of the multistage impactor in the test tube, i.e., the material delivered from the third stage to the filter in a next-generation impactor operated at a flow rate of 30 l / min. It is measured by the sum of.

As used herein, the term “inhibit” refers to the measurable alleviation of the degree or extent to which a phenomenon, condition or condition occurs or the tendency of the phenomenon, condition or condition to occur. The term "inhibit" or any form thereof is used in its broad sense and includes minimizing, preventing, reducing, suppressing, suppressing, limiting, restricting, limiting, slowing, and the like.

As used herein, "Mass median aerodynamic diameter" or "MMAD" refers to the aerosol diameter of an aerosol consisting of particles with 50% of aerosol mass having aerodynamic diameter smaller than MMAD. And MMAD is calculated according to Monograph 601 of United States Pharmacopeia (“USP”).

As referred to herein, the term “optical diameter” refers to the size of the particles measured by Fraunhofer diffraction mode using a laser diffraction particle size analyzer (eg Sympatec GmbH, Clausthal-Zellerfeld, Germany) equipped with a dry powder dispenser. .

The term solution mediated transformation refers to the dissolution of a more soluble form of a solid material (i.e. particles with short radius of curvature (driving force for Ostwald ripening) or amorphous material), Refers to the phenomenon of recrystallization into a more stable crystal form that can coexist in equilibrium with a saturated propellant solution.

"Patient" refers to an animal in which a combination of active agents as described herein exhibits a therapeutic effect. In one embodiment, the patient is a human.

“Perforated microstructures” are structural matrices that represent, outline, or include voids, voids, scratches, hollows, spaces, gap spaces, holes, perforations, or holes in which the surrounding suspension medium penetrates, fills, or permeates the microstructures. Suspending particles, such as those described in US Pat. No. 6,309,623 to Weers et al. The primary form of the perforated microstructure is generally not necessary, and any overall configuration that provides the desired formulation characteristics is implemented therein. Thus, in one embodiment, the perforated microstructures may comprise approximately spherical shapes, such as hollow, suspended, spray-dried microspheres. However, fine particles in which any primary form or aspect ratio has collapsed, corrugated, deformed or cracked may also be used.

In fact, for the suspended particles described herein, the perforated microstructures can be formed of any biocompatible material that does not substantially degrade or dissolve in the selected suspension medium. While a wide variety of materials can be used for particle formation, in some cases, the structural matrix associates with or includes surfactants such as phospholipids or fluorinated surfactants. Although not essential, the incorporation of compatible surfactants in the perforated microstructures or, more generally, the suspended particles, can improve the stability of respiratory dispersions, increase lung deposition, and facilitate the preparation of suspensions. Can be.

As used herein, the term “suspension medium” refers to a material that provides a continuous phase in which the active agent particles and suspension particles can be dispersed to provide a co-suspension formulation. Suspension media used in the co-suspension formulations described herein include propellants. As used herein, the term “propellant” refers to one or more pharmacologically inert substances that exert a sufficiently high vapor pressure at normal room temperature to propel a pharmaceutical from the canister of the MDI to the patient upon operation of the metering valve of the MDI. . Thus, the term “propellant” refers to both a single propellant and a combination of two or more different propellants that form a “propellant system”.

The term “suitable for breathing” generally refers to particles, clots, droplets, etc. that have been sized to inhale and reach the airways of the lungs.

As used herein to refer to the co-suspension composition described herein, the terms "physical stability" and "physically stable" are resistance to one or more of coagulation, aggregation and particle size changes due to solution mediated transition, and MMAD of suspension particles. And compositions capable of substantially maintaining fine particle dosages. In one embodiment, physical stability can be assessed through the application of the composition to accelerated degradation conditions, such as the temperature cycling described herein.

When referring to an active agent, the term “strong” refers to an active agent that is therapeutically effective at doses ranging from about 0.01 mg / kg to about 1 mg / kg. Typical dosages of very potent active agents generally range from about 100 μg to about 100 mg.

When referring to an active agent, the term “very strong” refers to an active agent that is therapeutically effective at a dosage of about 10 μg / kg or less. Typical dosages of very potent active agents generally range up to about 100 μg.

The terms "suspension stability" and "stable suspension" refer to suspension formulations capable of maintaining the properties of the co-suspension of the active particles and suspension particles over a period of time. In one embodiment, suspension stability can be measured via delivery dose uniformity, achieved by the co-suspension composition described herein.

The term "substantially insoluble" means that the composition is completely insoluble in certain solvents or poorly soluble in certain solvents. The term "substantially insoluble" means that a particular solute has a solubility of less than 1 part per 100 parts of solvent. The term "substantially insoluble" refers to Remington: The Science and Practice of Pharmacy, 21st ed. Lippincott, Williams & Wilkins, 2006, p. "Weakly soluble" (100 to 1000 parts of solvent per part of solute), "very weakly soluble" (1000 to 10,000 parts of solvent per part of solute) and "virtually insoluble" (10,000 parts per part of solute) shown in Table 16-1 More solvent).

As used herein, the term “surfactant” refers to any agent that preferentially adsorbs at the interface between two immiscible phases, such as the interface between water and the organic polymer solution, the water / air interface or the organic solvent / air interface. . Surfactants generally have a hydrophilic portion and a lipophilic portion that tend to present a moiety for a continuous phase that does not attract similarly coated particles upon adsorption to the fine particles, thus resulting in particle aggregation. Decrease. In some embodiments, the surfactant may also promote adsorption of the drug and increase the bioavailability of the drug.

A "therapeutically effective amount" refers to an amount of a compound that achieves therapeutic effectiveness by inhibiting a disease or disorder in a patient or by prophylactically inhibiting or preventing the onset of the disease or disorder. A therapeutically effective amount may somewhat relieve one or more symptoms of the disease or disorder in the patient; Partially or completely return one or more physiological or biochemical variables associated with or causing the disease or disorder to normal; It may be in an amount that reduces the likelihood of developing a disease or disorder.

The terms "chemically stable" and "chemical stability" refer to the full chromatography, in accordance with the limits (eg, ICH guidance Q3B (R2)) in which the individual degradation products of the active agent are specified by regulations during the shelf life of the product for human use. It refers to a co-suspension formulation that remains below 1% of the peak area and has an acceptable mass balance (eg, defined in ICH guidance Q1E) between the active agent assay and the total degradation product.

II . Composition

The compositions described herein are co-suspensions comprising two or more active agents and comprise a suspension medium, one or more active particles, and one or more suspension particles. Of course, if desired, the compositions described herein may include one or more additional ingredients. In addition, variations and combinations of the components of the compositions described herein can be used.

The co-suspension composition according to the present disclosure may be implemented by several different formulations. In certain embodiments, the compositions described herein comprise a first active agent provided in active agent particles co-suspended with one or more suspending particles comprising a second active agent. In another embodiment, the compositions described herein comprise two or more active agents provided in two or more different active agent particles co-suspended with one or more suspending particles comprising an active agent different from that contained in any of the active particles. do. In still further embodiments, the compositions described herein comprise two or more different active agent particles that are co-suspended with one or more of the suspended particles comprising the active agent, which may be the same or different from that contained in any of the active particles. It includes two or more active agents provided in. In another further embodiment, the compositions described herein comprise two or more active agents provided in two or more different active agent particles co-suspended with one or more suspended particles without active agent. If the composition described herein comprises two or more active particles, the composition may be referred to as a "composite" co-suspension. For example, a composition comprising two active agent particles co-suspended with one or more suspending particles may be referred to as a double co-suspension and three active agents co-suspended with one or more suspending particles. Compositions comprising particles may be referred to as triple co-suspensions and the like.

In the compositions according to the present specification, even when different kinds of different active agent particles are present in the composition, the active particles exhibit association with the suspended particles to the extent that the active particles and the suspended particles coexist in the suspension medium. Generally, due to the difference in density between the particles and the distinct species of the medium in which the particles are suspended (e.g., propellant or propellant system), buoyancy is higher than the propellant and creaming of particles with a lower density than the propellant. Causes sedimentation of particles with density. Thus, in suspensions consisting of mixtures of particles of various species with different densities or aggregation tendencies, the behavior of sedimentation or creaming is expected to be specific for each of the different particle types, leading to the separation of different particle types in the suspension medium. do.

However, the combination of propellant, activator particles and suspending particles described herein provides a co-suspension comprising the combination of two or more active agents in which the activator particles and suspending particles coexist in the propellant (ie, the suspending particles and the activator). Activator particles associate with the suspended particles such that the particles do not exhibit substantial separation from one another, for example by differential sedimentation or creaming, even after sufficient time for the formation of a cream or sedimentation layer). In certain embodiments, for example, the compositions described herein are amplified by centrifugation at temperature fluctuations and / or overspeeds, such as accelerations up to 1 g, 10 g, 35 g, 50 g and 100 g. When applied to buoyancy, the suspended particles are associated with the active agent particles to form the remaining co-suspension. However, the co-suspensions described herein need not be defined or limited to specific limiting forces. For example, the co-suspension contemplated herein is such that when the active particles and the suspending particles associate, there is no substantial separation of the active particles and suspension particles in the continuous phase formed by the suspension medium under conventional patient use conditions. Can be achieved successfully.

The co-suspension of the active agent particles and suspension particles according to the present specification provides the desired chemical stability, suspension stability and active agent delivery characteristics. For example, in certain embodiments, when present in an MDI canister, the co-suspension described herein may inhibit one or more of the following: aggregation of the active agent material; Differential sedimentation or creaming of active agent particles and suspension particles; Solution mediated transition of the active agent material; Chemical degradation of the components of the formulation, including an active agent material or surfactant; And loss of active agent to the surface of the vessel closure system, in particular the metering valve component. Quality work to achieve and ensure aerosol performance as co-suspension formulations achieves the desired fine particle fraction, fine particle dosage and delivery dose uniformity characteristics, and emptying the MDI canister containing the co-suspension formulation. It is delivered from the MDI to remain substantially throughout. In addition, the co-suspension according to the present disclosure provides a relatively simple HFA suspension medium that does not require modification, for example by addition of cosolvents, antisolvents, solvating agents or auxiliaries, even when the active agent is delivered at sufficiently different dosages. In use, it is possible to provide physically and chemically stable formulations which provide for constant administration characteristics of two or more active agents. In addition, compositions prepared as described herein, when delivered from MDI, eliminate or substantially eliminate the pharmaceutical effects commonly experienced with formulations comprising complex active agents. For example, as described by the specific embodiments described herein, the combination formulations described herein, when formulated and delivered separately, provide for each active agent contained in the formulation comparable to the delivery characteristics of the same active agent. Provide delivery features.

Providing co-suspensions according to the present disclosure may also simplify formulation, delivery and administration of the desired active agent. Without wishing to be bound by a particular theory, the delivery, physical stability and administration of the active agents included in such dispersions can be controlled by controlling the size, composition, shape and relative amounts of the active particles contained in such dispersions, by achieving a co-suspension of the active particles and suspension particles. It can be controlled substantially through, and is believed to be less dependent on the size and shape of the activator particles. In addition, in certain embodiments, the pharmaceutical compositions described herein may be formulated with non-CFC propellants or propellant systems substantially free of antisolvents, solvating agents, cosolvents, or auxiliaries.

Co-suspension compositions formulated according to the present teachings can inhibit physical and chemical degradation of the active agents contained therein. For example, in certain embodiments, the compositions described herein can inhibit one or more of chemical degradation, aggregation, coagulation, and solution mediated modification of the active agents included in the composition. The chemical and suspension stability provided by the co-suspension compositions described herein is such that even when one or more of the active agents delivered are very potent and the delivered doses of each of the active agents vary considerably, the dosage is preferred over the discharge of the MDI canister. To be distributed in such a way as to achieve uniformity ("DDU").

Co-suspension compositions as described herein can achieve at least ± 30% DDU for each active agent included therein. In one such embodiment, the compositions described herein achieve a DDU of at least ± 25% for each active agent included therein. In another such embodiment, the compositions described herein achieve a DDU of at least ± 20% for each active agent included therein. Moreover, the co-suspension composition according to the present disclosure contributes to substantially preserving FPF and FPD performance throughout the discharge of the MDI canister, even after being subjected to accelerated degradation conditions. For example, compositions according to the present disclosure maintain as much as 80%, 90%, 95% or more of the original FPF and FPD performance even after being subjected to accelerated degradation conditions.

The co-suspension compositions described herein provide the additional advantage of achieving this performance while formulated with non-CFC propellants. In certain embodiments, the compositions described herein can be used in one or more non-CFC propellants without the need to modify the characteristics of the non-CFC propellant, such as by adding one or more cosolvents, antisolvents, solubilizers, adjuvants or other propellant modifying materials. Formulated with suspension media containing only CFC propellants, achieving one or more of the targeted DDUs, FPFs, and FPDs.

(i) suspension medium

Suspension media included in the compositions described herein include one or more propellants. In general, suitable propellants for use as suspension media can be liquefied under pressure at room temperature and are propellant gases that are safe and toxicologically harmless upon inhalation or topical application. In addition, the selected propellant is preferably relatively unreactive with the suspended particles or the active particles. Exemplary compatible propellants include hydrofluoroalkane (HFA), perfluorinated compounds (PFC), and chlorofluorocarbons (CFC).

Specific examples of propellants that can be used to form suspension media of the co-suspensions disclosed herein include 1,1,1,2-tetrafluoroethane (CF ₃ CH ₂ F) (HFA-134a), 1,1 , 1,2,3,3,3-heptafluoro-n-propane (CF ₃ CHFCF ₃ ) (HFA-227), perfluoroethane, monochloro-fluoromethane, 1,1-difluoroethane And combinations thereof. Moreover, suitable propellants include, for example: short chain hydrocarbons; C _{1 -4} hydrogen-carbon-containing chlorofluorocarbons such as _{CH 2 ClF, CCl 2 FCHClF,} CF 3 CHClF, CHF 2 CClF 2, CHClFCHF 2, CF 3 CH 2 Cl, and CClF ₂ CH _3; C _{1 -4} hydrogen-containing carbon with fluoro (e.g., HFA), for example, _{CHF 2 CHF 2, CF 3 CH} 2 F, CHF 2 CH 3, and CF ₃ CHFCF _3; And perfluorocarbons such as CF ₃ CF ₃ and CF ₃ CF ₂ CF _{3 .}

Specific fluorocarbons, or fluorinated compound classes, that can be used as the suspension medium include, but are not limited to, fluoroheptane, fluorocycloheptane, fluoromethylcycloheptane, fluorohexane, fluorocyclohexane, fluoropentane, fluorocyclopentane, Fluoromethylcyclopentane, fluorodimethylcyclopentane, fluoromethylcyclobutane, fluorodimethylcyclobutane, fluorotrimethylcyclobutane, fluorobutane, fluorocyclobutane, fluoropropane, fluoroether, fluoropoly Ethers and fluorotriethylamines include, but are not limited to. The compounds may be used alone or in combination with more volatile propellants.

In addition to the fluorocarbons and hydrofluoroalkanes mentioned above, various exemplary chlorofluorocarbons and substituted fluorinated compounds can also be used as suspension medium. In this embodiment, FC-11 (CCl ₃ F), FC-11 B1 (CBrCl ₂ F), FC-11B2 (CBr ₂ ClF), FC12B2 (CF ₂ Br ₂ ) in view of the possible environmental effects that may be present , FC21 (CHCl ₂ F), FC21B1 (CHBrClF), FC-21B2 (CHBr ₂ F), FC-31B1 (CH ₂ BrF), FC113A (CCl ₃ CF ₃ ), FC-122 (CClF ₂ CHCl ₂ ), FC -123 (CF ₃ CHCl ₂ ), FC-132 (CHClFCHClF), FC-133 (CHClFCHF ₂ ), FC-141 (CH ₂ ClCHClF), FC-141B (CCl ₂ FCH ₃ ), FC-142 (CHF ₂ CH ₂ Cl), FC-151 (CH ₂ FCH ₂ Cl), FC-152 (CH ₂ FCH ₂ F), FC-1112 (CClF = CClF), FC-1121 (CHCl = CFCl) and FC-1131 (CHCl = CHF) can be used. Likewise, each of these compounds may be used alone or in combination with other compounds (ie, less volatile fluorocarbons) to form the stabilized suspensions disclosed herein.

In some embodiments, the suspension medium may be formed of a single propellant. In other embodiments, a combination of propellants may be used to form the suspension medium. In some embodiments, relatively volatile compounds may be mixed with lower vapor pressure components to provide a suspension medium having certain physical characteristics selected to improve the stability or enhance the bioavailability of the dispersed active agent. In some embodiments, lower vapor pressure compounds will include fluorinated compounds (eg, fluorocarbons) having boiling points higher than about 25 ° C. In some embodiments, lower vapor pressure fluorinated compounds for use in suspension media include perfluorooctylbromide C ₈ F ₁₇ Br (PFOB or perflubron), dichlorofluorooctane C ₈ F ₁₆ Cl ₂ , Perfluorooctylethane C ₈ F ₁₇ C ₂ H ₅ (PFOE), perfluorodecylbromide C ₁₀ F ₂₁ Br (PFDB) or perfluorobutylethane C ₄ F ₉ C ₂ H ₅ . In certain embodiments, such lower vapor pressure compounds are present at relatively low levels. The compounds may be added directly to the suspension medium or associated with the suspended particles.

Suspension media included in the compositions described herein may be formed of propellants or propellant systems that are substantially free of additional materials, including, for example, antisolvents, solvating agents, cosolvents, or auxiliaries. For example, in some embodiments, the suspension medium may be formed of a non-CFC propellant or propellant system substantially free of additional material, such as an HFA propellant or propellant system. This embodiment simplifies the formulation and preparation of a pharmaceutical composition suitable for respiratory delivery of the active agent included in the co-suspension composition.

However, in other embodiments, depending on the choice of propellant, the nature of the suspended particles, or the nature of the active agent delivered, the suspension medium used may include materials other than propellant or propellant systems. The additional material may include, for example, one or more suitable antisolvents, solubilizers, cosolvents or auxiliaries for the formulation to control vapor pressure, stability or solubility of suspended particles. For example, propane, ethanol, isopropyl alcohol, butane, isobutane, pentane, isopentane or dialkyl ethers such as dimethyl ether can be incorporated into the propellant in the suspension medium. Similarly, the suspension medium may contain volatile fluorocarbons. In other embodiments, one or both of polyvinylpyrrolidone ("PVP") or polyethylene glycol ("PEG") may be added to the suspension medium. Addition of PVP or PEG to the suspension medium may achieve one or more desired functional characteristics, for example PVP or PEG may be added to the suspension medium as a crystal growth inhibitor. In general, where volatile cosolvents or auxiliaries are used, up to about 1% w / w of the suspension medium the volatile cosolvents or auxiliaries may be selected from known hydrocarbon or fluorocarbon materials. For example, when a cosolvent or adjuvant is incorporated into the suspension medium, the cosolvent or adjuvant may comprise less than about 0.01%, 0.1%, or 0.5% w / w of the suspension medium. If PVP or PEG is included in the suspension medium, the components may be included up to about 1% w / w, or they may comprise less than about 0.01%, 0.1%, or 0.5% w / w of the suspension medium.

( ii Activator Particles

The activator particles included in the co-suspension described herein are formed of a material that can be dispersed and suspended in a suspension medium and sized to facilitate delivery of particles suitable for respiration from the co-suspension. Thus, in one embodiment, the activator particles are provided with micronized material wherein at least 90 volume% of the activator particles exhibit an optical diameter of about 7 μm or less. In other embodiments, the activator particles are micronized material in which at least 90 volume percent of the activator particles exhibit an optical diameter selected from the range of about 7 μm to about 1 μm, about 5 μm to about 2 μm, and about 3 μm to about 2 μm. Is provided. In a further embodiment, the activator particles are provided with micronized material wherein at least 90 volume% of the activator particles exhibit an optical diameter selected from 6 μm or less, 5 μm or less, 4 μm or less, 3 μm or less. In another embodiment, the activator particles are provided in micronized material having at least 50 volume% of the activator particle material exhibiting an optical diameter of about 4 μm or less. In a further embodiment, the activator particles are provided in micronized material having at least 50 volume% of the activator particle material exhibiting an optical diameter selected from about 3 μm or less, about 2 μm or less, about 1.5 μm or less, and about 1 μm or less. . In another embodiment, the active agent particles are selected from the range of about 4 volume percent or more of the active agent particles from about 4 μm to about 1 μm, about 3 μm to about 1 μm, about 2 μm to about 1 μm, about 1.3 μm and about 1.9 μm It is provided as a micronized material exhibiting an optical diameter.

The active agent particles may be formed entirely of the active agent or may be formulated to include one or more active agent particles in combination with one or more excipients or adjuvants. In certain embodiments, the active agent present in the active agent particles may be wholly or substantially crystalline, ie most active molecule molecules are arranged in a regular repeating pattern over a long range of outer surfaces. In other embodiments, the active agent particles may comprise an active agent present in both the crystalline or amorphous state. In another embodiment, the activator particles may comprise an activator present in a substantially amorphous state, ie the activator molecule is generally amorphous and does not have a regular repeating arrangement that is maintained over a long range. In another embodiment, when two or more active agents are present as active particles, all such active agents may be present in crystalline or substantially crystalline form. In another embodiment with two or more existing active agents, one or more of the active agents may be present in crystalline or substantially crystalline form, and at least other active agents may be present in an amorphous state.

If the active agent particles described herein comprise two or more active agents in combination with one or more excipients or adjuvants, the excipients and adjuvants may be selected based on the chemical and physical properties of the active agent used. Moreover, suitable excipients for the formulation of active agent particles include those described herein in connection with suspension particles. In certain embodiments, for example, the active agent particles can be, for example, lipids, phospholipids, carbohydrates, amino acids, organic salts, peptides, proteins, alditol, synthetic or natural polymers, or surfactant materials described herein in connection with suspension particles. It can be formulated using the above.

In other embodiments, for example, the active agent may be added to a solution of one or more of lipids, phospholipids, carbohydrates, amino acids, metal salts, organic salts, peptides, proteins, altitol, synthetic or natural polymers, or surfactant materials and suspended particles. Spray-dried with suspending particles containing the active agent in the material forming the polymer.

Any suitable method may be employed to achieve micronized activator material for use as is or incorporation in the activator particles or suspension particles described herein. The methods include, but are not limited to, micronized, crystallized or recrystallized methods by milling or grinding methods and methods using precipitation from supercritical or near-supercritical solvents, spray drying, spray freeze drying or lyophilization. Patent references that teach suitable methods for obtaining micronized activator particles are described, for example, in US Pat. No. 6,063,138, US Pat. No. 5,858,410, US Pat. No. 5,851,453, US Pat. No. 5,833,891, US Pat. No. WO 2007/009164. Where the activator particles comprise an activator material formulated with one or more excipients or adjuvants, the micronized activator particles may be formed using one or more preliminary processes, which process may include activator particles having a desired size distribution and particle composition. Can be used to obtain.

Active agent particles may be provided at any suitable concentration in the suspension medium. For example, in some embodiments, the active agent particles can be present at a concentration of about 0.01 mg / ml to about 20 mg / ml. In certain embodiments, the active agent particles may be present at concentrations selected from about 0.05 mg / ml to about 20 mg / ml, about 0.05 mg / ml to about 10 mg / ml, and about 0.05 mg / ml to about 5 mg / ml. have.

Various treatments and prophylactic agents can be incorporated into the co-suspension compositions described herein. Exemplary active agents include those that can be administered in the form of aerosolized medicaments, wherein the active agents suitable for use in the compositions described herein can be dispersed in a selected suspension medium (eg, substantially maintaining the co-suspension formulation). Substantially insoluble or soluble in the suspension medium), which can form co-suspensions with the suspended particles, and can be present in the form or so formulated in such a way that absorption suitable for breathing in a physiologically effective amount is achieved. do. Active agents that can be used to form the active agent particles described herein can have a variety of biological activities.

Examples of specific active agents which may be included in the compositions according to the present disclosure are, for example, short-acting beta agonists such as bitolterol, carbuterol, phenoterol, hexoprelinin, isoprenin (isoproterenol), Levosalbutamol, Orsiprenerin (Metaproterenol), Pyrbuterol, Procaterol, Limiterol, Salbutamol (Albuterol), Terbutalin, Tolobuterol, Leproterol, Ipratropium And epinephrine; Long-acting β ₂ adrenergic receptor agonists (“LABA”) such as bambuterol, clenbuterol, formoterol, and salmeterol; Ultra long-acting β ₂ adrenergic receptor agonists such as caroterol, milbuterol, indacaterol and salinine- or indole-containing and adamantyl-induced β ₂ agonists; Corticosteroids such as beclomethasone, budesonide, ciclesonide, flunisolid, fluticasone, methyl-prednisolone, mometasone, prednisone and triamcinolone; Anti-inflammatory agents such as fluticasone propionate, beclomethasone dipropionate, flunisolide, budesonide, tripedan, cortisone, prednisone, prednisolone, dexamethasone, betamethasone, or triamcinolone acetonide; Antitussives such as noscarpine; Bronchodilators such as ephedrine, adrenaline, phenoterol, formoterol, isoprenin, metaproterenol, salbutamol, albuterol, salmeterol, terbutalin; And muscarinic antagonists, including long-acting muscarinic antagonists (“LAMA”), such as glycopyrrolate, dexylphylonium, scopolamine, trocarmide, pyrenzepine, dimenhydrinate, tiotropium, darotro It may be fume, aclidinium, trosfume, ipartopium, atropine, benzatropin, or oxytropium.

Where appropriate, the active agents provided in the compositions, including but not limited to those described in detail herein, are in the form of salts (eg, as alkali metal or amine salts or acid addition salts) or as esters or solvates (hydrates), derivatives or Can be used as the free base. In addition, the active agent can be in any crystalline form or isomeric form or a mixture of isomeric forms, for example pure enantiomers, mixtures of enantiomers, racemates or mixtures thereof. In this regard, the form of the active agent may be selected to optimize the activity and / or stability of the active agent and / or to minimize the solubility of the active agent in the suspension medium.

Because the compositions disclosed herein allow for reproducible delivery of very low doses of the active agent, in certain embodiments, the active agents included in the compositions described herein may be selected from one or more powerful or very potent active agents. For example, in certain embodiments, a composition described herein is a potent active agent delivered at a dosage selected from about 100 μg to about 100 mg, about 100 μg to about 10 mg, and about 100 μg to 1 mg per dose. It can include one or more. In other embodiments, the compositions described herein are potent delivered at a dosage selected from about 80 μg or less, about 40 μg or less, about 20 μg or less, about 10 μg or less, or about 10 μg to 100 μg per dose. Or very powerful active agents in combination of two or more. Additionally, in certain embodiments, the compositions described herein comprise two or more very potent active agents delivered at a dosage selected from about 0.1 to about 2 μg, about 0.1 to about 1 μg, and about 0.1 to about 0.5 μg per dose. It can be included in combination.

In certain embodiments, the compositions described herein comprise LABA activators. In one embodiment, the composition comprises a LABA active agent in combination with a LAMA active agent or a corticosteroid active agent. In another embodiment, the composition comprises a LAMA active agent in combination with a LABA active agent and a corticosteroid. In this embodiment, the LABA activator comprises, for example, bambuterol, clenbuterol, formoterol, salmeterol, caroterol, milbuterol, indacaterol and salinine- or indole- and adamantyl -Inducing β ₂ agonists, and any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In certain embodiments, the active agent is selected from formoterol and its pharmaceutically acceptable salts, esters, isomers or solvates.

Formoterol can be used to treat inflammatory or obstructive pulmonary diseases and disorders, such as those described herein. The chemical name of formoterol is (±) -2-hydroxy-5-[(1RS) -1-hydroxy-2-[[(1RS) -2- (4-methoxyphenyl) -1-methylethyl] -Amino] ethyl] formanilide and are commonly used in pharmaceutical compositions as racemic fumarate dihydrate salts. Where appropriate, formoterol can be used in the form of salts (for example alkali metal or amine salts or acid addition salts), esters or solvates (hydrates). In addition, the formoterol can be in any crystalline or isomeric form or a mixture of isomeric forms, for example pure enantiomers, mixtures of enantiomers, racemates or mixtures thereof. In this context, the form of formoterol may be chosen to optimize the activity and / or stability of formoterol and / or to minimize the solubility of formoterol in the suspension medium. Pharmaceutically acceptable salts of formoterol include, for example, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as fumaric acid, maleic acid, acetic acid, lactic acid, citric acid, tartaric acid, ascorbic acid, succinic acid. , Glutaric acid, gluconic acid, tricarballylic, oleic acid, benzoic acid, p-methoxybenzoic acid, salicylic acid, o- and p-hydroxybenzoic acid, p-chlorobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid And salts of 3-hydroxy-2-naphthalene carboxylic acid. Hydrates of formoterol are described, for example, in US Pat. No. 3,994,974 and US Pat. No. 5,684,199. Certain crystalline forms are described, for example, in WO 95/05805 and certain isomers of formoterol are described in US Pat. No. 6,040,344.

In certain embodiments, the formoterol material used to form the formoterol particles is formoterol fumarate, and in one such embodiment the formoterol fumarate is in dihydrate form. If the composition described herein comprises formoterol, in certain embodiments, the composition described herein comprises about 0.5 μg to about 30 μg, 0.5 μg to about 1 μg, about 1 μg to about 10 per operation of MDI. Formoterol at a concentration that achieves a delivery dose selected from μg, about 2 μg to 5 μg, about 2 μg to about 10 μg, about 5 μg to about 10 μg, and 3 μg to about 30 μg. have. In another embodiment, a composition described herein has a delivery dose selected from about 30 μg or less, about 10 μg or less, about 5 μg or less, about 2.5 μg or less, about 2 μg or less or about 1.5 μg or less per operation of MDI. Formoterol may be included in an amount sufficient to provide. If the composition described herein comprises formoterol as an active agent to achieve a delivery dosage as described herein, in certain embodiments, the amount of formoterol included in the composition is for example from about 0.01 mg / ml to about 1 mg / ml, about 0.01 mg / ml to about 0.5 mg / ml, and about 0.03 mg / ml to about 0.4 mg / ml.

If the pharmaceutical co-suspension composition described herein comprises a LABA active agent, in certain embodiments, the active agent may be selected from salmeterol and any pharmaceutically acceptable salts, esters, isomers or solvating agents thereof. Salmeterol can be used to treat inflammatory or obstructive pulmonary diseases and disorders, such as those described herein. In addition, when salmeterol is included as a LABA activator, in some such embodiments, the composition may also include a LAMA or corticosteroid active. In another embodiment, the composition comprises salmeterol in combination with a LAMA activator and a corticosteroid. Salmeterol, pharmaceutically acceptable salts of Salmeterol, and methods of making the same are described, for example, in US Pat. No. 4,992,474, US Pat. No. 5,126,375, and US Pat. No. 5,225,445.

When salmeterol is included as a LABA activator, in certain embodiments, the compositions described herein comprise salmeterol at about 2 μg to about 120 μg, about 4 μg to about 40 μg, about 8 μg to And at a concentration that achieves a delivery dose selected from 20 μg, about 8 μg to about 40 μg, about 20 μg to about 40 μg, and 12 μg to about 120 μg. In another embodiment, the compositions described herein comprise salmeterol from about 120 μg or less, about 40 μg or less, about 20 μg or less, about 10 μg or less, about 8 μg or less, or about 6 μg or less per operation of MDI. It may be included in an amount sufficient to provide a delivery dose of choice. In order to achieve a targeted delivery dosage as described herein, where the composition described herein comprises salmeterol as an active agent, in certain embodiments, the amount of salmeterol included in the composition is, for example, about 0.04 mg / Ml to about 4 mg / ml, about 0.04 mg / ml to about 2.0 mg / ml, and about 0.12 mg / ml to 0.8 mg / ml. For example, the compositions described herein are sufficient to provide a targeted delivery dosage selected from about 4 μg to about 120 μg, about 20 μg to about 100 μg, and about 40 μg to about 120 μg per operation of the MDI. May include salmeterol. In another embodiment, the compositions described herein comprise salmeterol sufficient to provide a targeted delivery dosage of salmeterol selected from about 100 μg or less, about 40 μg or less, or about 15 μg or less per operation of MDI. It may include.

In certain embodiments, the compositions described herein comprise long-acting muscarinic antagonists (LAMA) active agents. Examples of LAMA activators that can be used in the compositions described herein include glycopyrrolate, dexipyrronium, tiotropium, throsfum, aclidinium and darotropium, and any pharmaceutically acceptable salts thereof, Esters, isomers or solvates. In some embodiments, the compositions described herein comprise LAMA active agents in combination with LABA active agents or corticosteroids. In other embodiments, the compositions described herein comprise LAMA active agents in combination with both LABA and corticosteroid actives. If the composition comprises a LAMA active agent, in certain embodiments, glycopyrrolate and any pharmaceutically acceptable salts, esters, isomers or solvates thereof may be selected.

Glycopyrrolate can be used to treat inflammatory or obstructive pulmonary diseases and disorders such as those described herein. As a choline inhibitor, glycopyrrolate provides an advantageous antisecretory effect for use in the treatment of lung diseases and disorders characterized by increased mucosal secretion. Glycopyrrolate is a quaternary ammonium salt. If appropriate, glycopyrrolate may be used in the form of salts (eg, alkali metal or amine salts, or acid addition salts), esters, solvates (hydrates) or selected isomers. In addition, glycopyrrolate may be in any crystalline form or in isomeric form or in a mixture of isomeric forms, for example pure enantiomers, mixtures of enantiomers, racemates or mixtures thereof. In such context, the form of glycopyrrolate may be selected to optimize the activity and / or stability of glycopyrrolate and / or to minimize the solubility of glycopyrrolate in the suspension medium. Suitable counter ions are, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate , Maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate Pharmaceutically acceptable counter ions, including 3-hydroxynaphthalene-2-carboxylate, methanesulfonate and benzenesulfonate. In certain embodiments of the compositions described herein, the bromide salt of glycopyrrolate, i.e. 3-[(cyclopentyl-hydroxyphenylacetyl) oxy] -1,1-dimethylpyrrolidinium bromide, is used, which is described in US Pat. It may be prepared according to the procedure shown in 2,956,062.

If the composition described herein comprises glycopyrrolate, in certain embodiments, the composition comprises about 10 μg to about 100 μg, about 15 μg to about 100 μg, about 15 μg to about 80 μg, per operation of MDI, and Sufficient glycopyrrolate to provide a delivery dosage selected from about 10 μg to about 80 μg. In another such embodiment, the formulation is glyco sufficient to provide a delivery dose selected from about 100 μg or less, about 80 μg or less, about 40 μg or less, about 20 μg or less, or about 10 μg or less per operation of the MDI. Pyrrolate. In another embodiment, the formulation comprises sufficient glycopyrrolate to provide a delivery dosage selected from about 9 μg, 18 μg, 36 μg and 72 μg per operation of the MDI. In order to achieve delivery dosages as described herein, where the composition described herein comprises glycopyrrolate as an active agent, in certain embodiments, the amount of glycopyrrolate included in the composition is, for example, about 0.04 mg / From ml to about 2.25 mg / ml.

In other embodiments, tiotropium and any pharmaceutically acceptable salts, esters, isomers or solvates thereof may be selected as LAMA activators for inclusion in the composition as described herein. Tiotropium is a known long-acting choline inhibitor suitable for use in the treatment of diseases or disorders associated with lung inflammation or obstruction, such as those described herein. Crystalline and pharmaceutically acceptable salt forms of tiotropium and tiotropium are described, for example, in US Pat. No. 5,610,163, US Pat. No. RE39820, US Pat. No. 6,777,423, and US Pat. No. 6,908,928. If the composition described herein comprises tiotropium, in certain embodiments, the composition comprises about 2.5 μg to about 25 μg, about 4 μg to about 25 μg, about 2.5 μg to about 20 μg, per operation of MDI, and Sufficient tiotropium to provide a delivery dosage selected from about 10 μg to about 20 μg. In other such embodiments, the formulation is sufficient to provide a delivery dose of thiotropium selected from about 25 μg or less, about 20 μg or less, about 10 μg or less, about 5 μg or less or about 2.5 μg per operation of the MDI. It includes. In another embodiment, the formulation comprises sufficient tiotropium to provide a delivery dosage selected from about 3 μg, 6 μg, 9 μg, and 18 μg per operation of the MDI. In order to achieve a delivery dosage as described herein, where the composition described herein comprises tiotropium as the active agent, in certain embodiments, the amount of tiotropium included in the composition is, for example, about 0.01 mg / ml To about 0.5 mg / ml.

In another embodiment, the compositions described herein comprise corticosteroids. Such active agents are, for example, beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and triamcinolone, and any pharmaceutically acceptable salts thereof , Esters, isomers or solvates. In some embodiments, the composition comprises a corticosteroid active in combination with a LAMA or LABA active. In another embodiment, the composition comprises a corticosteroid active in combination with a LAMA and LABA active. If the composition comprises a corticosteroid active, in certain embodiments, mometasone may be selected.

Mometasone, pharmaceutically acceptable salts of mometasone, such as mometasone furoate, and the preparation of such materials are known and are described, for example, in US Pat. No. 4,472,393, US Pat. No. 5,886,200, and US Patent No. 6,177,560. Mometasone is suitable for use in the treatment of diseases or disorders associated with lung inflammation or obstruction, such as those described herein (eg, US Pat. No. 5,889,015, US Pat. No. 6,057,307, US Pat. No. 6,057,581). US Patent No. 6,677,322, US Patent No. 6,677,323 and US Patent No. 6,365,581).

If the composition described herein comprises mometasone, in certain embodiments, the composition is about 20 μg to about 400 μg, about 20 μg to about 200 μg, about 50 μg to about 200 μg, about Mometasone and any pharmaceutically acceptable salt thereof in an amount sufficient to provide a targeted delivery dosage selected from 100 μg to about 200 μg, about 20 μg to about 100 μg, about 50 μg to about 100 μg, Esters, isomers or solvates. In another embodiment, a composition described herein is mometasone and its amount in an amount sufficient to provide a targeted delivery dosage selected from about 400 μg or less, about 200 μg or less, or about 100 μg or less per operation of MDI. And any pharmaceutically acceptable salts, esters, isomers or solvates.

In another embodiment, the compositions described herein comprise corticosteroids selected from fluticasone and budesonide. Both fluticasone and budesonide are suitable for use in the treatment of conditions associated with pulmonary inflammation or obstruction, such as those described herein. Fluticasone, pharmaceutically acceptable salts of fluticasone, such as fluticasone propionate, and the preparation of such materials are known and are described, for example, in US Pat. No. 4,335,121, US Pat. No. 4,187,301, And US Patent Publication No. US2008125407. Budesonide is also well known and is described, for example, in US Pat. No. 3,929,768. In certain embodiments, the compositions described herein are sufficient to provide a targeted delivery dosage selected from about 20 μg to about 200 μg, about 50 μg to about 175 μg, and about 80 μg to about 160 μg per operation of MDI. Amount fluticasone and any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In other embodiments, the compositions described herein influenza in an amount sufficient to provide a targeted delivery dosage selected from about 175 μg or less, about 160 μg or less, about 100 μg or less, or about 80 μg or less per operation of MDI. Ticason and any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In certain embodiments, the compositions described herein are sufficient to provide a targeted delivery dosage selected from about 30 μg to about 240 μg, about 30 μg to about 120 μg, and about 30 μg to about 50 μg per operation of MDI. Budesonide and any pharmaceutically acceptable salts, esters, isomers or solvates thereof in amounts. In another embodiment, the compositions described herein are budesonide and any thereof in amounts sufficient to provide a targeted delivery dosage selected from about 240 μg or less, about 120 μg or less, or about 50 μg or less per operation of MDI. Pharmaceutically acceptable salts, esters, isomers or solvates.

In each embodiment, the composition as described herein comprises two or more active agents. In some embodiments, the composition comprises a combination of two or more active agent particles that can be co-suspended with a single species of suspended particles. Alternatively, the composition may include two or more active particles co-suspended with two or more different suspended particles. As another alternative, a composition as described herein may comprise a single species of suspended particles and a single species of active particles suspended, wherein the single species of active particles comprise one or more active agents, Suspended particles include one or more active agents. In addition, a composition as described herein may comprise two or more active agents combined with a single species of active agent particle. For example, when the active agent particles are formulated using one or more excipients or auxiliaries in addition to the active agent material, the active agent particles may comprise individual particles comprising two or more different active agents.

( iii ) suspension  Particles

Suspension particles comprised in the co-suspension compositions described herein serve to facilitate stabilization and delivery of the active agents included in the composition. Although various forms of suspending particles can be used, the suspending particles are typically formed from a pharmacologically inert material that is acceptable for inhalation and substantially insoluble in the propellant to be screened. In general, the size of most of the suspended particles falls within a range suitable for breathing. Thus, in certain embodiments, the MMAD of the suspended particles does not exceed about 10 μm but is less than about 500 nm. In an alternate embodiment, the MMAD of the suspended particles is between about 5 μm and about 750 nm. In another embodiment, the MMAD of the suspended particles is about 1 μm to about 3 μm. When used in embodiments for nasal delivery from MDI, the MMAD of the suspended particles is between 10 μm and 50 μm.

In order to include suspending particles suitable for respiration in the MMAD range described, the suspended particles typically exhibit a volume median optical diameter of about 0.2 μm to about 50 μm. In one embodiment, the suspended particles exhibit a volume median optical diameter of about 25 μm or less. In another embodiment, the suspended particles exhibit a volume median optical diameter selected from about 0.5 μm to about 15 μm, about 1.5 μm to about 10 μm, and about 2 μm to about 5 μm.

The concentration of suspended particles included in the composition according to the present disclosure can be adjusted, for example, depending on the amount of active agent particles and suspension medium used. In one embodiment, the suspended particles are in the suspension medium from about 1 mg / ml to about 15 mg / ml, from about 3 mg / ml to about 10 mg / ml, 5 mg / ml to about 8 mg / ml, and about 6 And at a concentration selected from mg / ml. In another embodiment, the suspended particles are included in the suspension medium at a concentration of about 30 mg / ml or less. In another embodiment, the suspended particles are included in the suspension medium at a concentration of about 25 mg / ml or less.

The relative amount of suspension particles relative to the active agent particles is selected to achieve the co-suspension as contemplated herein. The co-suspension composition can be achieved when the amount of suspended particles measured by mass exceeds the amount of active agent particles. For example, in certain embodiments, the ratio of the total mass of suspended particles to the total mass of active particles may be about 3: 1 to about 15: 1, or alternatively about 2: 1 to 8: 1. Alternatively, the ratio of the total mass of the suspended particles to the total mass of the active particles is greater than about 1, such as about 1.5 or less, about 5 or less, about 10 or less, about 15 or less, depending on the nature of the suspended particles and the active particles used. , About 17 or less, about 20 or less, about 30 or less, about 40 or less, about 50 or less, about 60 or less, about 75 or less, about 100 or less, about 150 or less, and about 200 or less. In further embodiments, the ratio of the total mass of the suspended particles to the total mass of the active particles is about 10 to about 200, about 60 to about 200, about 15 to about 60, about 15 to about 170, about 15 to about 60, about 16, about 60, about 170.

In another embodiment, the amount of suspended particles measured by mass is less than the amount of active agent particles. For example, in certain embodiments, the mass of the suspended particles can be as low as 20% of the total mass of the active particles. However, in some embodiments, the total mass of the suspended particles may also be about the same or the same as the total mass of the activator particles.

Suspended particles suitable for use in the compositions described herein may be formed from one or more pharmaceutically acceptable materials or excipients that are suitable for inhaled delivery and that are not substantially degraded or dissolved in the suspension medium. In one embodiment, the perforated microstructures as defined herein can be used as suspending particles. Exemplary excipients that can be used in the formulations of the suspension particles described herein include, but are not limited to, (a) carbohydrates such as monosaccharides such as fructose, galactose, glucose, D-mannose, sorbose, and the like; Disaccharides such as sucrose, lactose, trehalose, cellobiose and the like; Cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin; And polysaccharides such as raffinose, maltodextrin, dextran, starch, chitin, chitosan, inulin and the like; (b) amino acids such as alanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine, leucine, isoleucine, valine and the like; (c) metals and organic salts prepared from organic acids and bases such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, and the like; (d) peptides and proteins such as aspartame, trileucine, human serum albumin, collagen, gelatin and the like; (e) alditol such as mannitol, xylitol and the like; (f) synthetic or natural polymers or combinations thereof, such as polylactide, polylactide-glycoside, cyclodextrin, polyacrylate, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydrides, polylactams, polyvinyl Pyrrolidone, hyaluronic acid, polyethylene glycol; And (g) surfactants, including fluorinated and non-fluorinated compounds, such as saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, and combinations thereof. In certain embodiments, the suspended particles can comprise calcium salts, such as calcium chloride, for example as described in US Pat. No. 7,442,388.

In addition, phospholipids from natural or synthetic sources can be used to prepare suspension particles suitable for use in the compositions described herein. In certain embodiments, the selected phospholipids will exhibit a phase transition from gel to liquid crystal above about 40 ° C. Exemplary phospholipids are relatively long chain (ie, C ₁₆ -C ₂₂ ) saturated lipids and may include saturated phospholipids such as saturated phosphatidylcholine (palmitoyl and stearoyl) having an acyl chain length of 16 C or 18 C. Exemplary phospholipids include phosphoglycerides such as dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidyl glycerol, short chain phosphatidylcholine, long chain saturated phosphatidyl ethanolamine, long chain saturated phosphatidylcetilin, Glycerol, and long chain saturated phosphatidylinositol. Further excipients are disclosed in International Patent Publication Nos. WO 96/32149 and US Pat. Nos. 6,358,530, 6,372,258 and 6,518,239.

In certain embodiments, suspended particles can be formed using one or more lipids, phospholipids or sugars as described herein. In some embodiments, the suspended particles comprise one or more surfactants. The use of suspending particles formed from or comprising one or more surfactants may promote absorption of the selected active agents, thereby increasing bioavailability. Suspended particles described herein, eg, suspended particles formed using one or more lipids, can be formed to exhibit the desired surface wrinkles (roughness), further reducing the surface area available for particle-particle interactions. Thereby enhancing aerosolization and reducing interparticle interactions. In further embodiments, where appropriate, naturally occurring lipids in the lung can be used to form suspended particles, which suspended particles have the potential to reduce opsonization (and then reduce phagocytosis by alveolar macrophages). Thus providing a long-lived controlled release particle in the lung.

In other embodiments, the suspended particles used in the compositions described herein can be selected to increase the storage stability of selected active agents similar to those disclosed in International Patent Publication No. WO 2005/000267. For example, in one embodiment, the suspended particles can comprise pharmaceutically acceptable glass stabilized excipients having a Tg of at least 55 ° C, at least 75 ° C, or at least 100 ° C. Glass stabilizing excipients suitable for use in the compositions described herein include, but are not limited to, trileucine, sodium citrate, sodium phosphate, ascorbic acid, inulin, cyclodextrin, polyvinyl pyrrolidone, mannitol, sucrose, trehalose, lactose, and proline It includes at least one of. Examples of additional glass-forming excipients are disclosed in US Pat. Nos. RE 37,872, 5,928,469, 6,258,341, and 6,309,671.

Suspension particles can be designed, sized and shaped as desired to provide the desired stability and active agent delivery characteristics. In one exemplary embodiment, the suspended particles comprise perforated microstructures as described herein. The perforated microstructures can be formed using one or more excipients as described herein when used as suspending particles in the compositions described herein. For example, in certain embodiments, the perforated microstructures may comprise one or more of the following: lipids, phospholipids, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and their Combinations, especially those approved for lung use. Specific surfactants that can be used to make the perforated microstructures include poloxamer 188, poloxamer 407, and poloxamer 338. Other specific surfactants include oleic acid or alkali salts thereof. In one embodiment, the perforated microstructures comprise greater than about 10% w / w surfactant.

In some embodiments, the suspended particles are prepared by forming an oil-in-water emulsion using fluorocarbon oils (eg, perfluorooctyl bromide, perfluorodecalin) that can be emulsified using surfactants such as long chain saturated phospholipids. Can be. The resulting underwater perfluorocarbon emulsion can be processed using a high pressure homogenizer to reduce the oil droplet size. Perfluorocarbon emulsions can optionally be supplied with the activator solution into the spray dryer if it is desired to include the activator in the matrix of the perforated microstructures. As is well known, spray drying is a single step process that converts a liquid feed into dry particulate form. Spray drying has been used to provide pharmaceutical material powders for various routes of administration, including aspiration. The operating conditions of the spray dryer (eg inlet and outlet temperature, feed rate, atomization pressure, flow rate of dry air and nozzle configuration) can be adjusted to produce the desired particle size that yields the yield of the resulting dry microstructure. Exemplary methods of making perforated microstructures are disclosed in US Pat. No. 6,309,623 to Weers et al.

Perforated microstructures as described herein can also be formed through lyophilization and subsequent milling or micronization. Lyophilization is a freeze-drying process in which water is sublimed from a composition after it is frozen. This process can be dried without raising the temperature. In another further embodiment, the suspended particles can be prepared using a spray freeze drying process, as disclosed in US Pat. No. 5,727,333.

In addition, suspension particles as described herein may include bulking agents such as polymer particles. Polymers by polymerization may be formed from biocompatible and / or biodegradable polymers, copolymers or blends. In one embodiment, polymers capable of forming aerodynamically light particles such as functionalized polyester graft copolymers and biodegradable polyanhydrides can be used. For example, polyester based bulk erosion polymers comprising poly (hydroxy acids) can be used. Polyglycolic acid (PGA), polylactic acid (PLA) or copolymers thereof may be used to form the suspended particles. The polyester may comprise charged or functional groups such as amino acids. For example, suspension particles can be formed from poly (D, L-lactic acid) and / or poly (D, L-lactic acid-co-glycolic acid) (PLGA) comprising a surfactant such as DPPC.

Other potential candidate polymers for use in suspension particles include polyamides, polycarbonates, polyalkylenes such as polyethylene, polypropylene, poly (ethylene glycol), poly (ethylene oxide), poly (ethylene terephthalate), Polyvinyl compounds such as polyvinyl alcohol, polyvinyl ether, and polyvinyl esters, polymers of acrylic acid and methacrylic acid, cellulose and other polysaccharides, and peptides or proteins, or copolymers or combinations thereof. The polymer may be selected or modified to have adequate stability and degradation rate in vivo for different controlled drug delivery applications.

The composition described herein may comprise two or more suspension particles. Furthermore, the composition according to the invention may comprise suspended particles comprising one or more active agents incorporated into the suspended particles. If the active agent is incorporated into the suspended particles, the suspended particles will be of a size suitable for breathing and can be formulated and prepared using, for example, the methods and materials described herein.

Compositions formulated according to the present teachings can inhibit degradation of the active agents contained therein. For example, in certain embodiments, the compositions described herein inhibit one or more of agglomeration, coagulation and solution mediated modification of the active agent material included in the composition. The pharmaceutical compositions described herein provide for respiratory delivery through MDI in a manner that achieves the desired delivery dosage uniformity (“DDU”) of each active agent included in combination with two or more active agents, even powerful and very powerful active agents. Suitable. As described in detail in the Examples included herein, even when delivering two or more active agents at very low doses, the compositions described herein provide at least ± 30% DDU for each active agent throughout the discharge of the MDI canister. Can be achieved. In one such embodiment, the compositions described herein achieve a DDU of at least ± 25% for each active agent throughout the discharge of the MDI canister. In another such embodiment, the compositions described herein achieve a DDU for an active agent of at least ± 20% for each active agent throughout the discharge of the MDI canister.

The pharmaceutical compositions described herein also contribute to substantially preserving FPF and FPD performance throughout the discharge of the MDI canister, even after being subjected to accelerated degradation conditions. For example, the compositions according to the present disclosure maintain as much as 80%, 90%, 95% or more of the original FPF and FPD performance throughout the discharge of the MDI canister, even after being subjected to accelerated decomposition conditions. . The compositions described herein are formulated using non-CFC propellants and provide the additional benefit of achieving this performance without or substantially eliminating the combinatorial effects often encountered in compositions incorporating multiple active agents. In certain embodiments, the compositions described herein may be modified with one or more non-CFCs without the need to modify the characteristics of the non-CFC propellants, such as by adding one or more cosolvents, antisolvents, solubilizers, adjuvants or other propellant modifying materials. Formulated using a suspension medium containing only propellant, achieving one or both of the targeted DDU, FPF and FPD performance.

In one embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Glycopyrrolate and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in the suspension medium at a concentration sufficient to provide a delivery dosage of about 15 μg to about 80 μg of glycopyrrolate per operation of the quantitative aspirator Activator particles of a first type comprising a cargo; Formoterol and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in suspension medium at a concentration sufficient to provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator Second type of activator particles comprising a cargo; And perforated microstructures suitable for breathing, the first and second species of active particles associated with the plurality of suspended particles, and a perforated microstructure exhibiting a volume median optical diameter of about 1.5 μm to about 10 μm. To form a co-suspension. In one such embodiment, the ratio of the total mass of suspended particles to the total mass of active particles of the first and second species is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Tiotropium suspended in suspension medium and any pharmaceutically acceptable salts, esters, isomers or solvents thereof in a concentration sufficient to provide a delivery dosage of about 5 μg to about 20 μg of tiotropium per operation of the quantitative aspirator Activator particles of a first type comprising a cargo; Formoterol and pharmaceutically acceptable salts, esters, isomers or solvates thereof suspended in the suspension medium at a concentration sufficient to provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator. Activator particles of a second type comprising; And perforated microstructures, the perforated microstructures exhibiting a volume median optical diameter of about 1.5 μm to about 10 μm, wherein the first and second types of active particles are associated with the plurality of suspended particles. Thereby forming a co-suspension. In one such embodiment, the ratio of the total mass of the suspended particles to the total mass of the active particles of the first and second species is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Glycopyrrolate and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in the suspension medium at a concentration sufficient to provide a delivery dosage of about 15 μg to about 80 μg of glycopyrrolate per operation of the quantitative aspirator A plurality of activator particles comprising a cargo; And a plurality of breathable suspension particles suitable for breathing, including formoterol and any pharmaceutically acceptable salts, esters, isomers or solvates thereof, the plurality of suspension particles having a volume center of from about 1.5 μm to about 10 μm Is included in the suspension medium at a concentration sufficient to provide an optical diameter and provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator, associated with the plurality of active agent particles to form a co-suspension box. In one such embodiment, the ratio of the total mass of the suspended particles to the total mass of the active particles of the first and second species is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Tiotropium suspended in suspension medium and any pharmaceutically acceptable salts, esters, isomers or solvents thereof in a concentration sufficient to provide a delivery dosage of about 5 μg to about 20 μg of tiotropium per operation of the quantitative aspirator A plurality of activator particles comprising a cargo; And a plurality of breathable suspension particles suitable for breathing, including formoterol and any pharmaceutically acceptable salts, esters, isomers or solvates thereof, the plurality of suspension particles having a volume center of from about 1.5 μm to about 10 μm Is included in the suspension medium at a concentration sufficient to provide an optical diameter and provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator, associated with the plurality of active agent particles to form a co-suspension box. In one such embodiment, the ratio of the total mass of the suspended particles to the total mass of the active particles of the first and second species is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Glycopyrrolate and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in the suspension medium at a concentration sufficient to provide a delivery dosage of about 15 μg to about 80 μg of glycopyrrolate per operation of the quantitative aspirator Activator particles of a first type comprising a cargo; Formoterol and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in suspension medium at a concentration sufficient to provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator Second type of activator particles comprising a cargo; Selected from beclomethasone, budesonide, ciclesonide, flunisolid, fluticasone, methyl-prednisolone, mometasone, prednisone and triamcinolone and any pharmaceutically acceptable salts, esters, isomers or solvates thereof Activator particles of the third kind comprising corticosteroids; And perforated microstructures comprising perforated microstructures exhibiting a volume median optical diameter of about 1.5 μm to about 10 μm, wherein the first, second and third types of active particles are a plurality of suspended particles. Associated with them to form a co-suspension. In one such embodiment, at least 90% by volume of the first, second and third species of active particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first, second and third species The ratio of the total mass of the active agent particles is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Glycopyrrolate and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in the suspension medium at a concentration sufficient to provide a delivery dosage of about 15 μg to about 80 μg of glycopyrrolate per operation of the quantitative aspirator Activator particles of a first type comprising a cargo; Formoterol and any pharmaceutically acceptable salts, esters, isomers or suspensions thereof in suspension medium at a concentration sufficient to provide a delivery dosage of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator Activator particles of the second kind comprising solvates; Comprising budesonide and any pharmaceutically acceptable salts, esters, isomers or solvates thereof suspended in the suspension medium at a concentration sufficient to provide a delivery dose of about 30 μg to about 50 μg of budesonide per operation of the quantitative aspirator. Third type of active agent particles; And perforated microstructures comprising perforated microstructures exhibiting a volume median optical diameter of about 1.5 μm to about 10 μm, wherein the first, second and third types of active particles are a plurality of suspended particles. Associated with them to form a co-suspension. In one such embodiment, at least 90% by volume of the first, second and third species of active particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first, second and third species The ratio of the total mass of the active agent particles is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Tiotropium suspended in suspension medium and any pharmaceutically acceptable salts, esters, isomers or solvents thereof in sufficient concentration to provide a delivery dosage of about 5 μg to about 20 μg of tiotropium per operation of the quantitative aspirator. Activator particles of a first type comprising a cargo; Formoterol and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in the suspension medium at a sufficient concentration to provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator. Second type of activator particles comprising a cargo; A budesonide and any pharmaceutically acceptable salts, esters, isomers or solvates thereof suspended in the suspension medium at a sufficient concentration to provide a delivery dose of about 30 μg to about 50 μg of budesonide per operation of the quantitative aspirator. Third type of active agent particles; And perforated microstructures comprising perforated microstructures exhibiting a volume median optical diameter of about 1.5 μm to about 10 μm, wherein the first, second and third types of active particles are a plurality of suspended particles. Associated with them to form a co-suspension. In one such embodiment, at least 90% by volume of the first, second and third species of active particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first, second and third species The ratio of the total mass of the active agent particles is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Glycopyrrolate and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in the suspension medium at a concentration sufficient to provide a delivery dosage of about 15 μg to about 80 μg of glycopyrrolate per operation of the quantitative aspirator Activator particles of a first type comprising a cargo; Formoterol and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in suspension medium at a concentration sufficient to provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator Second type of activator particles comprising a cargo; Mometasone and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in the suspension medium at a concentration sufficient to provide a delivery dose of about 20 μg to about 100 μg of mometasone per operation of the quantitative aspirator Third type of activator particles comprising a cargo; And perforated microstructures comprising perforated microstructures exhibiting a volume median optical diameter of about 1.5 μm to about 10 μm, wherein the first, second and third types of active particles are a plurality of suspended particles. Associated with them to form a co-suspension. In one such embodiment, at least 90% by volume of the first, second and third species of active particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first, second and third species The ratio of the total mass of the active agent particles is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Tiotropium suspended in suspension medium and any pharmaceutically acceptable salts, esters, isomers or solvents thereof in a concentration sufficient to provide a delivery dosage of about 5 μg to about 20 μg of tiotropium per operation of the quantitative aspirator Activator particles of a first type comprising a cargo; Formoterol and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in suspension medium at a concentration sufficient to provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator Second type of activator particles comprising a cargo; Mometasone and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in the suspension medium at a concentration sufficient to provide a delivery dose of about 20 μg to about 100 μg of mometasone per operation of the quantitative aspirator Activator particles of the third kind comprising a cargo; And perforated microstructures comprising perforated microstructures exhibiting a volume median optical diameter of about 1.5 μm to about 10 μm, wherein the first, second and third types of active particles are a plurality of suspended particles. Associated with them to form a co-suspension. In one such embodiment, at least 90% by volume of the first, second and third species of active particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first, second and third species The ratio of the total mass of the active agent particles is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Glycopyrrolate and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in the suspension medium at a concentration sufficient to provide a delivery dosage of about 15 μg to about 80 μg of glycopyrrolate per operation of the quantitative aspirator Activator particles of a first type comprising a cargo; Formoterol and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in suspension medium at a concentration sufficient to provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator Second type of activator particles comprising a cargo; And beclomethasone, budesonide, ciclesonide, flunisolidide, fluticasone, methyl-prednisolone, mometasone, prednisone and triamcinolone and any pharmaceutically acceptable salts, esters, isomers or solvates thereof A plurality of suspending particles suitable for breathing comprising a perforated microstructure comprising a corticosteroid selected from said suspension particles exhibiting a volume median optical diameter of from about 1.5 μm to about 10 μm and of the first and second species Associate with activator particles to form a co-suspension. In one such embodiment, at least 90% by volume of the first and second species of activator particles exhibit an optical diameter of less than 7 μm, the total mass of suspended particles versus the total mass of the first and second species of activator particles. The ratio is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Glycopyrrolate and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in the suspension medium at a concentration sufficient to provide a delivery dosage of about 15 μg to about 80 μg of glycopyrrolate per operation of the quantitative aspirator Activator particles of a first type comprising a cargo; Formoterol and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in suspension medium at a concentration sufficient to provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator Second type of activator particles comprising a cargo; And a plurality of suspending particles suitable for breathing, including perforated microstructures including budesonide and any pharmaceutically acceptable salts, esters, isomers or solvates thereof, the suspension particles being about 30 per operation of the quantitative aspirator. Comprising sufficient budesonide to provide a delivery dose of budesonide from μg to about 50 μg, exhibiting a volume median optical diameter of about 1.5 μm to about 10 μm, and co-associated with the first and second species of active particles Forming a suspension. In one such embodiment, at least 90% by volume of the first and second species of activator particles exhibit an optical diameter of less than 7 μm, the total mass of suspended particles versus the total mass of the first and second species of activator particles. The ratio is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Glycopyrrolate and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in the suspension medium at a concentration sufficient to provide a delivery dosage of about 15 μg to about 80 μg of glycopyrrolate per operation of the quantitative aspirator Activator particles of a first type comprising a cargo; Formoterol and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in suspension medium at a concentration sufficient to provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator Second type of activator particles comprising a cargo; And a plurality of suspending particles suitable for respiration, including perforated microstructures comprising mometasone and any pharmaceutically acceptable salts, esters, isomers or solvates thereof, the suspending particles per actuating of the quantitative aspirator. Comprising sufficient mometasone to provide a delivery dose of about 20 μg to about 100 μg of mometasone, exhibiting a volume median optical diameter of about 1.5 μm to about 10 μm, and wherein the first and second species of active particles Associated with them to form a co-suspension. In one such embodiment, at least 90% by volume of the first and second species of activator particles exhibit an optical diameter of less than 7 μm, the total mass of suspended particles versus the total mass of the first and second species of activator particles. The ratio is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Tiotropium suspended in suspension medium and any pharmaceutically acceptable salts, esters, isomers or solvents thereof in a concentration sufficient to provide a delivery dosage of about 5 μg to about 20 μg of tiotropium per operation of the quantitative aspirator Activator particles of a first type comprising a cargo; Formoterol and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in suspension medium at a concentration sufficient to provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator Second type of activator particles comprising a cargo; And from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and triamcinolone and any pharmaceutically acceptable salts, esters, isomers or solvates thereof A plurality of suspending particles suitable for respiration comprising a perforated microstructure comprising a selected corticosteroid, the suspended particles exhibiting a volume median optical diameter of about 1.5 μm to about 10 μm, Associate with activator particles to form a co-suspension. In one such embodiment, at least 90% by volume of the first and second species of activator particles exhibit an optical diameter of less than 7 μm, the total mass of suspended particles versus the total mass of the first and second species of activator particles. The ratio is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Tiotropium suspended in suspension medium and any pharmaceutically acceptable salts, esters, isomers or solvents thereof in a concentration sufficient to provide a delivery dosage of about 5 μg to about 20 μg of tiotropium per operation of the quantitative aspirator Activator particles of a first type comprising a cargo; Formoterol and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in suspension medium at a concentration sufficient to provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator Second type of activator particles comprising a cargo; And a plurality of suspending particles suitable for breathing, including perforated microstructures including budesonide and any pharmaceutically acceptable salts, esters, isomers or solvates thereof, the suspension particles being about 30 per operation of the quantitative aspirator. Comprising sufficient budesonide to provide a delivery dose of budesonide from μg to about 50 μg, exhibiting a volume median optical diameter of about 1.5 μm to about 10 μm, and co-associated with the first and second species of active particles Forming a suspension. In one such embodiment, at least 90% by volume of the first and second species of activator particles exhibit an optical diameter of less than 7 μm, the total mass of suspended particles versus the total mass of the first and second species of activator particles. The ratio is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

In another embodiment, a co-suspension composition deliverable from a quantitative aspirator according to the present disclosure comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Tiotropium suspended in suspension medium and any pharmaceutically acceptable salts, esters, isomers or solvents thereof in a concentration sufficient to provide a delivery dosage of about 5 μg to about 20 μg of tiotropium per operation of the quantitative aspirator Activator particles of a first type comprising a cargo; Formoterol and any pharmaceutically acceptable salts, esters, isomers or solvents thereof suspended in suspension medium at a concentration sufficient to provide a delivery dose of from about 2 μg to about 10 μg of formoterol per operation of the quantitative aspirator Second type of activator particles comprising a cargo; And a plurality of suspending particles suitable for respiration, including perforated microstructures comprising mometasone and any pharmaceutically acceptable salts, esters, isomers or solvates thereof, the suspending particles per actuating of the quantitative aspirator. Comprising sufficient mometasone to provide a delivery dose of about 20 μg to about 100 μg of mometasone, exhibiting a volume median optical diameter of about 1.5 μm to about 10 μm, and wherein the first and second species of active particles Associated with them to form a co-suspension. In one such embodiment, at least 90% by volume of the first and second species of activator particles exhibit an optical diameter of less than 7 μm, the total mass of suspended particles versus the total mass of the first and second species of activator particles. The ratio is selected from about 3: 1 to about 15: 1 and about 2: 1 to 8: 1.

III . dose aspirator  system

As described in connection with the methods provided herein, the co-suspension compositions disclosed herein can be used in MDI systems. MDI is configured to deliver a specific amount of medicament in the aerosol form. In one embodiment, the MDI system includes a pressurized liquid formulation-filling canister disposed in an actuator formed from a mouthpiece. The MDI system may comprise a formulation described herein comprising a suspension medium, one or more active particles and one or more suspending particles. The canister used for the MDI can have any suitable configuration, and in one exemplary embodiment, the canister can have a volume in the range of about 5 ml to about 25 ml, for example the canister can have a 19 ml volume. Can be. After shaking the device, a mouthpiece is inserted into the mouth between the patient's lips and teeth. Patients typically breathe deeply, empty the lungs, and then slowly inhale while operating the cartridge.

Inside the exemplary cartridge, there is a metering chamber capable of holding a defined volume of formulation (e.g., 63 [mu] l or any other suitable volume available on commercial metering valves) that is discharged to the expansion chamber at the distal end of the valve stem during operation. There is a metering valve included. The actuator may include a port that holds the canister and also has an actuator nozzle that receives the valve stem of the metering valve. In operation, a specific volume of formulation moves into the expansion chamber, exits the actuator nozzle and into the high speed nebulizer and is drawn into the patient's lungs.

IV . Way

Provided herein are methods of formulating pharmaceutical compositions for respiratory delivery of two or more active agents. In one embodiment, the method comprises providing a suspension medium, one or more active particles and one or more suspended particles, and combining the components to form a composition, wherein the active particles are associated with the suspended particles. And co-placed with the suspended particles in the suspension medium to form a co-suspension as described herein. In one embodiment, the association of activator particles and suspension particles is such that they do not separate due to their different buoyancy in the propellant. As is known, the method of formulating a pharmaceutical composition as described herein may comprise providing two or more active particles in combination with one or more suspension particles. In further embodiments, the method may comprise providing two or more suspension particles in combination with two or more active particles in a manner to produce a co-suspension. In another embodiment, the one or more active particles can be combined with one or more suspension particles, as described herein. In certain embodiments, the activator material included in the activator particles is selected from one or more of LABA, LAMA or corticosteroid actives. In certain embodiments, the activator particles consist essentially of the activator material and are free of additional excipients, adjuvants, stabilizers, and the like.

In certain embodiments of a method of providing a stabilized composition of a combination of two or more active agents, the present disclosure provides a method of inhibiting solution mediated transfer of an active agent in a pharmaceutical composition for pulmonary delivery. In one embodiment, a suspension medium as described herein is obtained, such as a suspension medium formed by HFA propellant. Suspended particles are also obtained or prepared as described herein. Activator particles are also obtained and the suspension medium, the suspension particles and the activator particles are combined to form a co-suspension, wherein the activator particles are associated with the suspension particles and suspended particles in a continuous phase formed by the suspension medium. And co-located. Compared to the active agent particles contained in the same suspension medium in the absence of suspended particles, the co-suspension according to the present disclosure exhibits higher resistance to solution mediated phase transitions leading to irreversible crystal coagulation, thus improving stability and administration It has been found that amount uniformity can be derived.

In further embodiments, a method of forming a stabilized composition comprising two or more active agents for pulmonary delivery comprises protecting the FPF and / or FPD of the composition throughout the discharge of the MDI canister. In certain embodiments of the method for protecting FPF and / or FPD provided by the pharmaceutical composition for pulmonary delivery, ± 20%, ± 10%, or even ± of the initial FPD and / or FPF throughout the discharge of the MDI canister. There is provided a co-suspension suitable for breathing as described herein that can maintain FPD and / or FPF, respectively, within 5%. This performance can be achieved when two or more active agents are incorporated into the co-suspension, even after the co-suspension is subjected to accelerated degradation conditions. In one embodiment, a suspension medium as described herein is obtained, such as a suspension medium formed by HFA propellant. Suspended particles are also obtained or prepared as described herein. Activator particles are also obtained and the suspension medium, suspension particles and activator particles are combined to form a co-suspension, wherein the activator particles are associated with the suspended particles and co-located with the suspended particles in the suspension medium. Even after the composition has been exposed to one or more temperature cycling situations, the co-suspension is either FPD or FPF within ± 20%, ± 10%, or even ± 5% of each value measured before the composition is exposed to the complex temperature cycling situation. Keep it.

Disclosed are methods of making MDI for respiratory delivery of two or more active agents. In certain embodiments, the method comprises loading activator particles and suspending particles into a canister as described herein. The actuator valve may be attached to the end of the canister and the sealed canister. The actuator valve can be adjusted to disperse the metered amount of active agent included in the co-suspension composition per actuation of the MDI. The canister may be filled with a pharmaceutically acceptable suspension medium, such as a propellant as described herein, whereby the active agent particles and suspension particles yield a stable co-suspension in the suspension medium.

In a method comprising respiratory delivery of two or more active agents using the compositions described herein, the compositions may be delivered by MDI. Thus, in certain embodiments of the methods, an MDI loaded with the composition described herein is obtained, and two or more active agents are administered to the patient via respiratory delivery by the operation of the MDI. For example, in one embodiment involving pulmonary delivery of two or more active agents, after shaking the MDI device, the mouthpiece is inserted into the patient's mouth between the lips and the teeth. Patients typically breathe deeply and empty their lungs and then inhale slowly while operating the cartridges in the MDI. In operation, a specific volume of formulation moves into the expansion chamber, exits the actuator nozzle, into the high speed nebulizer and is drawn into the patient's lungs. In one embodiment, the dose of each active agent delivered throughout the discharge of the MDI canister is up to 30% less than the average delivered dose and more than 30% less than the average delivered dose. Thus, there is also provided a method of achieving a desired DDU of two or more active agents delivered from MDI. In this embodiment, the method comprises two or more delivered from an MDI selected from, for example, ± 30% or more DDUs, ± 25% or more DDUs, and ± 20% or more DDUs throughout the discharge of the co-suspension composition MDI canister. It may include achieving a DDU for each of the active agents.

Provided herein are methods of treating a patient suffering from an inflammatory or obstructive pulmonary disease or condition. In certain embodiments, the method comprises pulmonary delivery of the pharmaceutical composition described herein, and in certain embodiments, pulmonary administration of the pharmaceutical composition is performed by delivery of the composition using MDI. The disease or condition to be treated may be selected from, for example, any inflammatory or obstructive pulmonary disease or condition that responds to the administration of the active agents described herein. In some embodiments, the combination of active agents comprises one or more active agents selected from LAMA, LABA or corticosteroid active agents. In certain embodiments, the pharmaceutical compositions described herein include aggravation of airway hyperresponsiveness as a result of asthma, COPD, other drug therapy, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, disturbed breathing, dyspnea Can be used to treat syndromes, pulmonary arterial hypertension, pulmonary vasoconstriction, emphysema, and diseases or disorders selected from any other respiratory disease, condition, trait, genotype or phenotype that may respond to administration of a combination of active agents described herein. have. In certain embodiments, the pharmaceutical compositions described herein can be used to treat pulmonary inflammation and obstruction associated with cystic fibrosis.

In addition, the pharmaceutical compositions according to the present disclosure delivered from MDI provide desirable pharmacodynamic (PD) performance. In certain embodiments, pulmonary delivery of the pharmaceutical compositions described herein results in a rapid and significant increase in lung capacity, which may be characterized by an increase in the patient's effortful expiratory volume (FEV ₁ ) for one second. For example, in certain embodiments, a method of achieving a clinically significant increase in FEV ₁ , the method comprising providing a co-suspension composition comprising two or more active agents, wherein one or more of the active agents are described herein. Selected from LABA, LAMA or corticosteroid active agents as described), and administration of the composition to patients experiencing pulmonary inflammation or obstruction via MDI. In one such embodiment, the active agent included in the composition is selected from one of a combination of LABA and LAMA active agents, a combination of LABA and corticosteroid active agents, a combination of LAMA and corticosteroid active agents, and a combination of LABA, LAMA and corticosteroid active agents Combinations. For the purposes of this disclosure, the clinically significant increase in FEV ₁ is any increase of at least 100 ml, and in certain embodiments of the methods described herein, administering a composition according to the present disclosure to a patient within 1 hour or less. Cause a clinically significant increase in FEV ₁ . In this other embodiment, the method of administering a composition as described herein to a patient via MDI results in a clinically significant increase in FEV ₁ within 0.5 hours or less.

In further embodiments, a method is provided for achieving an increase in FEV ₁ of greater than 100 ml. For example, in certain embodiments, the methods described herein include methods for achieving at least 150 ml of FEV ₁ within a time selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less. In another embodiment, the methods described herein include methods for achieving at least 200 ml of FEV ₁ within a time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours or less. In other embodiments, the methods described herein include methods for achieving at least 250 ml of FEV ₁ within a time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours or less. In another embodiment, the methods described herein include methods for achieving at least 300 ml of FEV ₁ within a time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours or less. In another embodiment, the methods described herein include methods for achieving at least 350 ml of FEV ₁ within a time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours or less. In this particular embodiment, the active agent included in the composition is selected from one of a combination of LABA and LAMA activators, a combination of LABA and corticosteroid active agents, a combination of LAMA and corticosteroid active agents, and a combination of LABA, LAMA and corticosteroid active agents And the composition is delivered to the patient via MDI.

In another further embodiment, a method for achieving and maintaining a clinically significant increase in FEV ₁ is provided. In certain embodiments, when administering a single dose of a combination of active agents formulated in a composition as described herein to a patient via MDI, the clinically significant increase in FEV ₁ is 0.5 hours or less, 1 hour or less, 1.5 Achievement is achieved within a time selected from below time, and a clinically significant increase in FEV ₁ is maintained for up to 12 hours or more. In certain embodiments, the increase in FEV ₁ may be selected from at least 150 ml, at least 200 ml, at least 250 ml, at least 300 ml, and at least 350 ml, wherein the increase in FEV ₁ is up to 4 hours, up to 6 hours, It remains clinically significant for a time selected from up to 8 hours, up to 10 hours, and up to 12 hours. In certain embodiments, the active agent included in the composition is selected from one of a combination of LABA and LAMA activators, a combination of LABA and corticosteroid active agents, a combination of LAMA and corticosteroid active agents, and a combination of LABA, LAMA and corticosteroid active agents Combination, and the composition is delivered to the patient via MDI.

The compositions, systems and methods described herein are not only suitable for achieving desirable pharmacodynamic performance within a short time, but will also achieve these results in a high percentage of patients. For example, methods are provided for achieving at least a 10% increase in FEV ₁ in at least 50% of patients experiencing pulmonary inflammation or occlusion. For example, in certain embodiments, a method of achieving at least a 10% increase in FEV _{1 in} a patient provides a co-suspension composition comprising a combination of active agents, wherein the one or more active agents are LABAs as described herein. , LAMA, and corticosteroid active agents), and administering the composition to patients suffering from pulmonary inflammation or occlusion via MDI. In certain embodiments, administration of the composition results in at least 10% increase in FEV _{1 in} at least 50% of the patients within a time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours or less. In another embodiment, administration of the composition results in at least 10% increase in FEV _{1 in} at least 60% of the patients within a time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours or less. In another embodiment, administration of the composition results in at least a 10% increase in FEV _{1 in} at least 70% of the patients within a time selected from less than 0.5 hours, less than 1 hour, less than 1.5 hours, and less than 2 hours. In another embodiment, administration of the composition results in at least 10% increase in FEV _{1 in} at least 80% of the patients within a time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours or less. In certain embodiments, the active agent included in the composition is a combination selected from one of a combination of LABA and LAMA active agents, a combination of LABA and corticosteroid active agents, a combination of LAMA and corticosteroid active agents, and a combination of LABA, LAMA and corticosteroid active agents. Wherein the composition is delivered to the patient via MDI.

In certain embodiments, the methods described herein facilitate treatment of a patient who is experiencing lung inflammation or blockage, the method comprising providing a co-suspension composition comprising a combination of active agents as described herein And administering the composition via MDI to a patient experiencing pulmonary inflammation or obstruction, wherein administration of the composition via MDI results in an increase from baseline of at least 200 ml of FEV ₁ , or overall of at least 150 ml of FEV ₁ . Patients experiencing an increase of at least 12% from the baseline of FEV ₁ accompanied by an increase. In certain embodiments, the dose of the composition is increased from the above 200 ㎖ baseline in FEV _1, or 150 ㎖ more FEV less than the more than 12% from the reference line of FEV ₁ to involve the entire increase in ₁ hour, 1.5 hours, Resulting in at least 50% of patients within a time selected from 2 hours or less and 2.5 hours or less. In other embodiments, the dose of the composition is increased from the above 200 ㎖ baseline in FEV _1, or 150 ㎖ more FEV less than the more than 12% from the reference line of the FEV _1, following the total increase of ₁₁ hours, less than 1.5 hours At least 60% of patients within a time selected from 2 hours, and 2.5 hours or less. In another embodiment, the dose of the composition is increased from the above 200 ㎖ baseline in FEV _1, or a more than 12% from the reference line of the FEV _1, following the total increase of more than 150 ㎖ FEV ₁ 1.5 hours, less than 2 hours And at least 70% of patients within a time selected from less than 2.5 hours, and less than 3 hours. In another embodiment, the dose of the composition is increased from the above 200 ㎖ baseline in FEV _1, or a more than 12% from the reference line of the FEV _1, following the total increase of more than 150 ㎖ FEV ₁ 1.5 hours, less than 2 hours And at least 80% of patients within a time selected from less than 2.5 hours, and less than 3 hours. In certain embodiments, the active agent included in the composition is a combination selected from one of a combination of LABA and LAMA active agents, a combination of LABA and corticosteroid active agents, a combination of LAMA and corticosteroid active agents, and a combination of LABA, LAMA and corticosteroid active agents. Wherein the composition is delivered to the patient via MDI.

In some embodiments, an increase in FEV ₁ for the clinically way to achieve and maintain a significant increase in FEV ₁ described herein is only compared with the improvement provided by the composition to pass only a single active agent for the significant improvement in FEV ₁ Brings about. For the purpose of comparing the FEV ₁ performance of the compositions described herein with a composition that delivers only a single active agent, a significant improvement of FEV ₁ is an improvement of at least 60 ml. For example, in certain embodiments, a method of achieving significant improvement in FEV ₁ over an improvement provided by a composition delivering only a single active agent comprises a co-suspension composition as described herein comprising a combination of active agents. Providing (the one or more active agents are selected from LABA, LAMA, and corticosteroid active agents as described herein), and administering the composition to a patient experiencing pulmonary inflammation or occlusion via MDI. In certain embodiments, administration of the co-suspension composition is FEV ₁ achieved by a composition delivering a single active agent. As compared to the AUC _{0 -12} 70 ㎖ more FEV ₁ AUC _{0 -} results in an improvement of _12. In another embodiment, the co-results in the improvement of _{12 -} administration of a suspension composition is more than 80 ㎖ FEV ₁ AUC ₀ as compared to the FEV ₁ AUC _{0 -12} is achieved by a composition for delivering a single active agent. In another embodiment, the co-results in the improvement of _{12 -} administration of the suspension composition of at least 90 ㎖ FEV ₁ AUC ₀ as compared to the FEV ₁ AUC _{0 -12} is achieved by a composition for delivering a single active agent.

In another embodiment, a method of achieving significant improvement in FEV ₁ over an improvement provided by a composition delivering only a single active agent comprises providing a co-suspension composition as described herein comprising a combination of active agents ( Said at least one active agent is selected from a LABA, LAMA, and corticosteroid active agent as described herein), and administering to a patient experiencing pulmonary inflammation or occlusion via said composition MDI, said administration being a single active agent. This results in a significant improvement of the peak FEV ₁ as compared to the FEV ₁ peak change (peak FEV ₁ ) achieved by the composition delivering. In certain embodiments, administration of the co-suspension composition as described herein results in an improvement of at least 70 ml of peak FEV ₁ as compared to peak FEV ₁ achieved by the composition delivering a single active agent. In another embodiment, administration of the co-suspension composition as described herein results in an improvement of at least 80 ml of peak FEV ₁ compared to the peak FEV ₁ achieved by the composition delivering a single active agent. In further embodiments, administration of the co-suspension composition as described herein results in an improvement of at least 90 ml of peak FEV ₁ as compared to peak FEV ₁ achieved by the composition delivering a single active agent.

Also provided are methods that provide a clinically significant increase in inspiratory dose (IC) in patients who are experiencing lung inflammation or obstruction. As used herein, IC is defined as the maximum volume of gas that can enter the lungs upon full inhalation following normal exhalation, and the clinically significant increase in IC is an increase of at least 70 ml. For example, in certain embodiments, a method of improving an IC as described herein provides a co-suspension composition as described herein comprising a combination of active agents, wherein the one or more active agents are described herein. Selected from LABA, LAMA, and corticosteroid active agents), and administering the composition via MDI to a patient experiencing pulmonary inflammation or occlusion, wherein administration of the composition results in an increase in IC of at least 70 ml. do. In certain embodiments, administration of the compositions according to the invention results in an increase in IC of at least 100 ml. In another embodiment, administration of the composition according to the invention results in an increase in IC of at least 200 ml. In another embodiment, administration of the composition according to the invention results in an increase of an IC of at least 300 ml, and in another embodiment, administration of the composition according to the invention results in an increase of an IC of at least 350 ml. In certain embodiments, the increase in IC is quickly experienced. For example, in each of the described methods, a clinically significant increase in IC or an increase in IC selected from at least 100 mL, at least 200 mL, at least 300 mL, or at least 350 mL is less than 1 hour and 2 hours in the patient. It can be experienced within a time selected from the following.

The methods of increasing IC described herein are useful not only to achieve a clinically significant increase in IC quickly within a short time, but also to maintain a clinically significant increase in IC over time. For example, as highlighted by the clinical results presented in Example 12, a clinically significant increase in IC provided by the methods described herein is experienced rapidly after administration by the patient, and the increase in IC is post-administration. It remains clinically significant for up to 12 hours or more, and the increase in IC remains clinically significant even after long term administration (eg, multiple consecutive dosing days).

In addition, the compositions according to the invention provide a significantly greater increase in IC than the increase in IC provided by the composition delivering only a single active agent. In an embodiment of the method of increasing IC described herein, administration of the co-suspension composition as described herein results in an increase in IC that is at least 70 ml greater than the increase in IC provided by the composition delivering only a single active agent. to provide. In one embodiment, the increase in IC provided by administering the co-suspension composition described herein is at least 100 ml greater than the increase in IC provided by the composition delivering only a single active agent. In another embodiment, the increase in IC provided by administering the co-suspension composition described herein is at least 125 ml greater than the increase in IC provided by the composition delivering only a single active agent.

In some embodiments, the methods described herein to achieve the desired pharmacodynamic effect are characterized by the delivery of a relatively small amount of active agent. In certain embodiments, for example, a method described herein to achieve a clinically significant increase in FEV ₁ is administered a co-suspension as described herein comprising a combination of glycopyrrolate and formoterol active agent. Wherein the co-suspension is administered to the patient via a quantitative aspirator up to twice a day, with a total delivered dose of up to 150 μg glycopyrrolate and up to 12 μg formoterol at each administration The delivery dose is administered to the patient. In another embodiment, a method described herein to achieve a clinically significant increase in FEV ₁ comprises administering a co-suspension as described herein comprising a combination of glycopyrrolate and formoterol active agent The co-suspension is administered to the patient no more than twice a day via a quantitative aspirator, with a total delivered dose of up to 100 μg glycopyrrolate and a total delivered dose of up to 12 μg formoterol at each dose. Is administered. In another embodiment, a method described herein to achieve a clinically significant increase in FEV ₁ comprises administering a co-suspension as described herein comprising a combination of glycopyrrolate and formoterol active agent The co-suspension is administered to the patient no more than twice a day via a quantitative aspirator, with a total delivered dose of up to 80 μg glycopyrrolate and a total delivered dose of up to 12 μg formoterol at each dose. Is administered. In another embodiment, a method described herein to achieve a clinically significant increase in FEV ₁ comprises administering a co-suspension as described herein comprising a combination of glycopyrrolate and formoterol active agent The co-suspension is administered to the patient no more than twice a day via a quantitative aspirator, with a total delivered dose of up to 50 μg glycopyrrolate and a total delivered dose of up to 12 μg formoterol at each dose. Is administered.

In some embodiments, a method of achieving a clinically significant increase in IC described herein comprises administering a co-suspension composition as described herein to a patient via a quantitative aspirator, wherein the co-suspension is glyco Comprising a pyrrolate and formoterol active agent, wherein the co-suspension is administered to the patient via a quantitative aspirator up to twice a day, with a total delivered dose of up to 150 μg of glycopyrrolate and up to 12 μg at each administration The total delivered dose of formoterol of is administered to the patient. In certain embodiments, for example, a method described herein to achieve a clinically significant increase in IC comprises administering a co-suspension as described herein comprising a combination of glycopyrrolate and formoterol active agent. Wherein the co-suspension is administered to a patient no more than twice a day via a quantitative aspirator, with a total delivery dose of up to 100 μg glycopyrrolate and a total delivery of up to 12 μg formoterol at each administration Dosage is administered to the patient. In another embodiment, the methods described herein for achieving a clinically significant increase in IC comprise administering a co-suspension as described herein comprising a combination of glycopyrrolate and formoterol active agent, The co-suspension is administered to the patient up to twice a day via a quantitative aspirator, with a total delivered dose of up to 80 μg glycopyrrolate and a total delivered dose of up to 12 μg formoterol at each dose. Administered. In another embodiment, the methods described herein for achieving a clinically significant increase in IC comprise administering a co-suspension as described herein comprising a combination of glycopyrrolate and formoterol active agent, The co-suspension is administered to the patient up to twice a day via a quantitative aspirator, with a total delivered dose of up to 50 μg glycopyrrolate and a total delivered dose of up to 12 μg formoterol at each dose. Administered.

Compositions provided and delivered in the methods described herein can include co-suspension compositions comprising any combination of active agents as described herein. For example, in certain embodiments, a method described herein to achieve a clinically significant increase in FEV ₁ or IC provides a co-suspension composition comprising two or more active agents, wherein one or more of the active agents Selected from LABA, LAMA or corticosteroid active agents as described above, and the composition comprises administering via MDI to a patient experiencing pulmonary inflammation or obstruction. In one embodiment, the active agent included in the co-suspension composition is one of a combination of LABA and LAMA activator, a combination of LABA and corticosteroid active agent, a combination of LAMA and corticosteroid active agent, and a combination of LABA, LAMA and corticosteroid active agent Combinations selected from. In certain embodiments of the methods described herein, the co-suspension compositions provided and administered may be any particular co-suspension composition described herein.

The specific examples included herein are for illustrative purposes only and should not be regarded as limiting the present disclosure. Moreover, the compositions, systems, and methods disclosed herein have been described in connection with specific embodiments thereof, and many of the details are set forth for purposes of illustration, and the present invention is likely to be embodied in further embodiments, the detailed description set forth herein It will be apparent to those skilled in the art that various changes may be made without departing from the spirit of the invention. Any of the active agents and reagents used in the examples below are either commercially available or can be prepared according to standard literature procedures by those skilled in the art of organic synthesis. The entire contents of all publications, patents, and patent applications referenced herein are hereby incorporated by reference.

Example  One

Exemplary co-suspension compositions as described herein were prepared and evaluated. The composition included a combination of glycopyrrolate (GP) and formoterol fumarate (FF) activator. GP was present in the propellant as micronized, crystalline activator particles. GP was co-suspended with spray dried suspension particles comprising FF disposed in the material forming the suspended particles. To achieve this, FF was dissolved in the feedstock used to prepare the lipid-based suspended particles.

GP activator particles were formed by micronizing glycopyrrolate using a jet mill. Particle size distribution of glycopyrrolate activator particles was measured by laser diffraction using a laser diffraction particle size analyzer, Fraunhofer diffraction mode, equipped with a dry powder dispenser (eg Sympatec GmbH, Clausthal-Zellerfeld, Germany). . 50% by volume of the activator particles exhibited an optical diameter of less than 1.7 μm and 90% by volume exhibited an optical diameter of less than 3.5 μm.

FF-containing suspended particles were prepared as follows: 654 mL of a fluorocarbon emulsion in water of PFOB (perfluorooctyl bromide) stabilized by phospholipids was prepared; Homogenize 26.5 g of phospholipid, DSPC (1,2-disteroyl-sn-glycero-3-phosphocholine), and 2.4 g of calcium chloride in 276 ml of hot water (80 ° C.) using a high shear mixer and; 142 mL of PFOB was added slowly during homogenization. The resulting coarse emulsion was then further homogenized using a high pressure homogenizer (Model C3, Avestin, Ottawa, CA) at a pressure of up to 170 MPa five times. 552 mg of FF was dissolved in 273 ml of lukewarm water (50 ° C.) and most of the solution was mixed with the emulsion using a high shear mixer. The emulsion was spray dried in nitrogen using the following spray drying conditions: inlet temperature 95 ° C .; Outlet temperature 68 ° C .; Emulsion feed rate 2.4 ml / min; And 498 l / min total gas flow rate. The final mass fraction of formoterol in the spray dried powder was 2%.

A second lot of FF-containing suspended particles was prepared in a similar manner. The mass fraction of FF in the spray dried powder was 1% relative to the lot. A third lot of suspended particles was made without FF.

The particle size distribution (VMD) of the suspended particles was measured by laser diffraction. For both lots of FF-containing suspended particles, 50% by volume was less than 3.5 μm and the geometric standard deviation of the distribution was 1.7. For suspended particles without FF, 50% by volume was less than 3.2 μm and the geometric standard deviation of the distribution was 1.8.

Activator particles and suspension particles of the target mass were weighed and placed in a 19 ml volume of fluorinated ethylene polymer (FEP) coated aluminum canister (Presspart, Blackburn, UK) to make MDI containing FF, GP or both. . The canister is crimp sealed using a 63 μl valve (# BK 357, Bespak, King's Lynn, UK) and 12.4 g of HFA 134a (1,1,1,2-tetrafluoro) by overpressure through the valve stem Ethane) (Ineos Fluor, Lyndhurst, UK). Suspension concentration results and target delivery dosages assuming an actuator deposition of 20% are presented in Table 1 for three different configurations (1A to 1C). After injecting propellant, the canister was sonicated for 15 seconds and shaken with a wrist movement shaker for 30 minutes. The canister was mounted on a polypropylene actuator with a 0.3 mm orifice (# BK 636, Bespak, King's Lynn, UK).

[Table 1a]

Composition of Glycopyrrolate-Formoterol Fumarate Combination Co-suspension of Example 1

Filled MDI was stored down the valve in two different conditions: refrigeration at 5 ° C. without overpacking, and controlled room temperature at 25 ° C./60% RH with foil overpacking. Aerosol performance and delivery dose uniformity tests were conducted at different time points. Aerosol performance was evaluated following preparation according to USP <601> (United States Pharmacopoeia Monograph 601). The particle size distribution was measured using a Next Generation Impactor (NGI) operated at a flow rate of 30 L / min. The sample canister was placed in the actuator in two consuming operations and two additional consuming priming operations. Five operations were collected on NGI with USP throat attached. Valves, actuators, inlets, NGI cups, stages, and filters were rinsed with volumetric dispensed solvents. Sample solutions were analyzed using drug specific chromatography. The fine particle fraction was defined using the sum from the third stage to the filter. A delivery dose uniformity test in use was performed using the Dose Uniformity Sampling Apparatus described in USP <601>. The aspirator was arranged and prepared as mentioned above. Two operations were collected and analyzed at the start of use, intermediate and end.

No trend was observed in terms of aerosol performance or delivery dose uniformity over the irradiation period (3 months) or with the storage temperature. Therefore, all aerosol performance test results were collected. Table 1b lists the average performance of the different configurations. The fine particle dose is the sum of the mass collected by the filter of the paddle in the third stage, normalized by the metered dose. Average aerosol performance for all three configurations was equivalent.

TABLE 1 b Average aerosol performance for co-suspension in Example 1

Dose content uniformity was tested over canister life for both active materials of the combination product. 1 and 2 show pre-actuator doses for configurations 1A and 1B, respectively, normalized by the actual metered dose of the canister. Assuming an actuator deposition of 20%, the target pre-actuator dose for both actives was 80%. Individual FF and GP doses are indicated by dots and triangles, respectively. The solid line represents the mean of the formoterol dose and the dashed line represents the mean of the glycopyrrolate dose. 3 and 4 show the ratio of normalized pre-actuator doses to configurations 1A and 1B, respectively. The results suggest that the dose ratio remained constant over the canister life. In addition, the variability of the dose ratio is much lower than the individual doses, suggesting that a co-suspension with a constant carrier-to-active ratio has been formed and maintained over the life of the container.

From the above results, it can be seen that when formulated according to the disclosure provided herein, a combination product co-suspension is formed with suspension particles comprising one of the active pharmaceutical ingredients, in this case FF. The suspension particle to active particle ratio can be adjusted to achieve target dose content uniformity while maintaining similar aerosol performance.

Example  2

MDIs containing FF, GP or both were prepared at target concentrations of 2.4-18 μg per operation for FF and GP, respectively. The GP activators were micronized and measured as laser diffraction, as described in Example 1, with d ₁₀ , d ₅₀ , d ₉₀ and widths of 0.6, 1.7, 3.6 and 1.9 μm, respectively. FF was incorporated into the spray dried suspension particles to prepare as described in Example 1 with a composition of 2% FF, 91.5% DSPC and 6.5% CaCl ₂ . Target amounts of active particles and suspension particles were weighed and placed in a 19 ml volume of fluorinated ethylene polymer (FEP) coated aluminum canister (Presspart, Blackburn, UK) to produce GP, FF and GP + FF MDI. The canister is press-sealed with a 50 μl valve (#BK 357, Bespak, King's Lynn, UK) and 10.2 g of HFA 134a (1,1,1,2-tetrafluoroethane) by overpressure through the valve stem Ineos Fluor, Lyndhurst, UK). After injecting propellant, the canister was sonicated for 15 seconds and shaken with a wrist movement shaker for 30 minutes. The canister was mounted on a polypropylene actuator with a 0.3 mm orifice (# BK 636, Bespak, King's Lynn, UK).

The long term aerosol stability and delivery characteristics of the MDI compositions were evaluated. In particular, under various conditions, the aerosol particle size distribution and delivery dose characteristics of such compositions were evaluated in accordance with USP <601> as described in Example 1 for extended periods of time up to 12 months. For example, as shown in FIG. 5, the delivery dose uniformity provided by the composition prepared in accordance with Example 1, for samples stored inside an aluminum foil pouch to minimize water entry into the MDI canister ( Ie “protected storage”), such compositions were substantially preserved even after 12 months storage at 5 ° C. or 4.5 months at 25 ° C. and 60% relative humidity (RH).

The aerosol performance of such compositions was also evaluated over unprotected storage conditions extended to 12 months and protected storage conditions extended to 6 months. As shown in FIG. 6, the GP and FP particle size distributions provided by this co-suspension composition continued substantially after 12 months protected storage at 5 ° C. or after 6 months unprotected storage at 25 ° C. and 60% RH. It became. As shown in FIG. 7, even under stress conditions (40 ° C., 75% RH), the particle size distribution of GP and FF delivered from the quantitative aspirator after 6 months showed no noticeable degradation.

To assess whether the combination of GP and FF in a single formulation results in a decrease in aerosol properties associated with a composition comprising a single active agent, the aerosol properties of the co-suspension composition were evaluated for suspension compositions comprising only a single active agent.

As can be seen in FIG. 8, the aerosol performance of the combination co-suspension composition comprising both GP and FF active agents is no different from the aerosol performance achieved by the suspension composition comprising GP or FF alone. It has been demonstrated that aerosol properties are substantially the same as those achieved from single component or dual combination co-suspensions.

Example  3

The pharmacokinetics and stability of the combination co-suspension quantitative aspirator containing glycopyrrolate and formoterol fumarate were evaluated clinically. The clinical trial was a single-center, randomized, double-blind, single dose, 4-timed, 4-treatment crossover study used to evaluate four inhalation treatments administered by MDI. Four treatments included delivery of FF inhalation aerosol immediately following continuous delivery of formoterol fumarate (FF) inhalation aerosol, glycopyrrolate (GP) inhalation aerosol, GP + FF inhalation aerosol, and GP inhalation aerosol. FF inhalation aerosols and GP inhalation aerosols as well as GP + FF inhalation aerosols were prepared as described in Example 2. GP + FF inhalation aerosols were also labeled with "fixed" combinations of GP and FF, while treatments requiring delivery of FF inhalation aerosols immediately after continuous delivery of GP inhalation aerosols were labeled with "unwinding" combinations of GP and FF.

Subjects were randomly ordered for study and assigned one of four treatment sequences, with each treatment sequence containing all four study treatments. Each subject received four single dose treatments separated by 7 to 21 days. Sixteen subjects were enrolled and analyzed for stability. Three subjects were excluded from the PK analysis because they did not receive one or more of the four treatments, and an additional two subjects were excluded from the PK analysis because they could not be assessed due to dosing errors resulting from poor inhalation techniques.

GP + FF inhalation aerosols were administered to each subject to provide 72 μg doses of GP and 9.6 μg doses of FF (4 runs, 18 μg GP and 2.4 μg FF per action). GP inhalation aerosols were administered to give each subject a 72 μg dose of GP (4 runs, 18 μg GP per run). FF inhalation aerosol was administered to give each subject a 9.6 μg dose of FF (4 runs, 2.4 μg FF per action). For blinding purposes, four operations of the placebo MDI were preceded before each of the three preceding treatments. A loose combination of GP inhalation aerosols after FF inhalation aerosol was administered to each subject to receive 72 μg of GP and 9.6 μg of FF (4 operations, 4 additional operations after 18 μg GP per operation, 2.4 μg FF per operation). Provided.

Both loose and fixed combinations of GP and FF were safe and well tolerated, and the fixed combination gave a stability profile similar to that observed for the other three treatments evaluated in the experiment. To measure plasma concentrations of GP and FF used to calculate several PK variables, blood samples were taken at 2, 5, 15, and 30 minutes full-dose, as well as 1, 2, 4, 6, 8, and 12 hours. Post-dose was collected. Plasma concentration time profiles for both GP and FF within 12 hours immediately after dosing are provided in FIG. 9. As can be seen in FIG. 9, administration of the fixed combination of GP and FF resulted in plasma concentrations of GP and FF after administration comparable to those produced after administration of the unwinding combination of GP and FF. As mentioned in vitro delivery dose and particle size distribution performance described in Example 2, no in vivo combination effect was observed for the fixed combination of GP + FF inhalation aerosol.

Example  4

An exemplary double co-suspension composition according to the present disclosure was prepared to prepare a quantitative aspirator comprising the composition. The composition included a combination of glycopyrrolate (GP) and formoterol fumarate (FF), each provided as a micronized crystalline material. Combination crystalline co-suspension MDI was prepared by semi-automated suspension filling. The double co-suspension consisted of a combination of two microcrystalline active pharmaceutical ingredients (also referred to as “APIs”), GP and FF, co-suspended with suspended particles in HFA 134a propellant. Dual co-suspensions were formulated to provide delivery doses of 18 μg GP per operation and 4.8 μg FF per operation. When preparing a double co-suspension composition, in certain compositions, the FF API material used is referred to as "crude", while in other compositions the FF API material used is referred to as "fine". Whether the co-suspension composition comprises crude or fine FF, the composition is formulated to provide a FF μg delivery dose per operation. Particle size characteristics for the crude FF, fine FF, and GP API used to formulate the co-suspension compositions described in this example are detailed in Table 2. In addition to the dual co-suspension compositions, monotherapy co-suspension compositions comprising only the FF active agent material were formulated. FF monotherapy co-suspensions utilized the crude FF API. Monotherapy MDI was prepared using the FF monotherapy co-suspension and formulated to formulate FF monotherapy MDI to provide a delivery dose of 4.8 μg FF per operation.

Feedstock concentration 80 with 93.44% DSPC (1,2-distaroyl-sn-glycero-3-phosphocholine) and 6.56% anhydrous calcium chloride (corresponding to 2: 1 DSPC: CaCl ₂ moles / molar ratio) Suspended particles were prepared through the spray-dried emulsion at mg / ml. In the emulsion preparation process, DSPC and CaCl ₂ were dispersed using a high shear mixer at 8000-10000 rpm in a vessel containing heated water (80 ± 3 ° C.) and PFOB was slowly added in the process. The emulsion was then treated six times in a high pressure homogenizer (10000-25000 psi). The emulsion was spray dried using a spray dryer equipped with a 0.42 "atomizer nozzle with an atomizer gas flow rate setpoint of 18 SCFM. The dry gas flow rate was 72 SCFM, the inlet temperature was 135 ° C, the outlet temperature was 70 ° C, and the emulsion flow rate was 58 ml. / Min.

For MDI preparation, the drug addition vessel (DAV) for suspension filling was prepared in the following manner: first half of the suspended particle amount was added, then the microcrystalline material was filled, and finally the other half of the suspended particles. Was added on top. Materials were added to the vessel in a humidity controlled environment of <10% RH. The DAV was then connected to a 4 L suspension vessel, flushed with HFA 134a propellant and gently mixed to form a slurry. The slurry was then returned to the suspension mixing vessel and diluted with additional HFA-134a to form a final suspension of the target concentration with gentle stirring with an impeller. The temperature inside the vessel was maintained at 21-23 ° C. throughout the entire batch production. After 30 minutes of recirculation, the suspension was charged to 14 ml of fluorinated ethylene polymer (FEP) coated aluminum canister (Presspart, Blackburn, UK) via a 50 μl valve (Bespak, King's Lynn, UK). Sample canisters were randomly selected for full canister analysis to ensure correct formulation amounts. The optical diameter and particle size distribution of two lots of micronized formoterol particles were measured as described in Example 1. Table 2 lists the d ₁₀ , d ₅₀ and d ₉₀ values for different lots of the micronized material used. d ₁₀ , d ₅₀ and d ₉₀ represent particle sizes for which the cumulative volume distribution reported by the particle size measuring instrument reaches 10%, 50% and 90%, respectively.

The particle size distribution provided by both double co-suspension formulations prepared according to Example 4 was compared with the particle size distribution prepared by the co-suspension composition prepared according to Example 1. The results of the comparison are provided in Table 3, where "% FPF FF" and "% FPF GP" represent the fine particle mass of the specific active agent for the third stage of the NGI up to the filter divided by the actuator mass and multiplied by 100. .

[Table 2]

Particle size distribution of micronized formoterol fumarate and glycopyrrolate used to prepare double co-suspension

[Table 3]

Particle Size Distribution for Different, Exemplary GP / FF Co-Suspensions

The aerosol performance of the double co-suspension composition prepared according to this example was evaluated and compared to the co-suspension composition prepared according to Example 1, and the aerosol performance was evaluated as described in Example 1. The results of this comparison are shown in FIGS. 10-12. As will be readily understood with reference to these figures, whether the crystalline formoterol material used to provide the double co-suspension is fine or crude, the FF and GP particle size distributions for the double co-suspension composition are given in Example 1 It was substantially the same as achieved by the co-suspension composition prepared accordingly.

In addition, the delivery dose uniformity for GP and FF provided by the dual co-suspension composition described in this Example was evaluated as described in Example 1. The evaluation result is shown in FIG. Since all operations delivered the expected dose within ± 25% of the mean, the double co-suspension formulation provided the desired DDU characteristics for both GP and FF.

Example  5

Described is a formulation of a dual co-suspension composition of salmeterol ginapoate (SX) activator particles and fluticasone propionate (FP) activator particles. Both FP and SX are present in the propellant as micronized crystalline particles. Two micronized activator particles were co-suspended with spray dried suspension particles.

Micronized SX (4-hydroxy-α1-[[[6- (4-phenylbutoxy) hexyl] amino] methyl] -1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate) Was obtained from the manufacturer (Inke SA, Germany) and used as activator particles. The particle size distribution of SX was measured by laser diffraction. 50% by volume of the micronized particles showed an optical diameter of less than 2 μm, and 90% by volume showed an optical diameter of less than 3.9 μm.

Micronized FP (S- (fluoromethyl) 6 ^α , 9-difluoro-11 ^β- 17-dihydroxy-16 ^α -methyl-3-oxoandrostar-1,4-diene-17 ^β -car Bothioate, 17-propionate) was obtained from the manufacturer (Hovione Farma Ciencia SA, Loures Portugal) and micronized to be used as activator particles. The particle size distribution of FP was measured by laser diffraction. 50% by volume of the micronized particles had an optical diameter of less than 2.6 μm, and 90% by volume had an optical diameter of less than 6.6 μm.

Suspension particles were prepared as follows: In-water-fluorocarbon emulsion of 150 ml PFOB (perfluorooctyl bromide) stabilized with phospholipids was prepared; Homogenize 12.3 g of phospholipid, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), and 1.2 g of calcium chloride using a high shear mixer in 100 ml of hot water (70 ° C.) Was done; 65 mL of PFOB was added slowly during homogenization. The resulting crude emulsion was then further homogenized three times using a high pressure homogenizer (Model C3, Avestin, Ottawa, CA) at a pressure of 140 MPa or less.

The emulsion was spray dried in nitrogen using the following spray drying conditions: inlet temperature 90 ° C., outlet temperature 69 ° C., emulsion feed rate 2.4 ml / min, total gas flow rate 498 L / min. The particle size distribution, VMD, of the suspended particles was measured by laser diffraction. 50 vol% of the suspended particles were smaller than 2.7 μm and the geometric standard deviation of the distribution was 2.0. In addition, the aerodynamic particle size distribution of the suspended particles was determined using a flight time particle size analyzer. 50% by volume of the suspended particles had an aerodynamic particle diameter of less than 1.6 μm. The large difference between the aerodynamic particle diameter and the optical diameter suggested that the suspended particles had a low particle density of <0.5 kg / l. This was confirmed by electron microscopy and showed a hollow, thin-walled morphology.

MDI was prepared by weighing the micronized FP, SX and suspended particles of the target mass into a 19 ml volume of fluorinated ethylene polymer (FEP) coated aluminum canister (Presspart, Blackburn, UK). The canister was press-sealed with a 63 μl valve (# BK 357, Bespak, King's Lynn, UK) and 10 mL of HFA 134a (1,1,1,2-tetrafluoroethane) by overpressure through the valve stem. (Ineos Fluor, Lyndhurst, UK). After injecting propellant, the canister was sonicated for 15 seconds and shaken with a wrist movement shaker for 30 minutes. The canister was mounted on a polypropylene actuator with a 0.3 mm orifice (# BK 636, Bespak, King's Lynn, UK). Aerosol performance was prepared according to USP 601 and evaluated immediately as described previously in Example 1. The results are reported in Table 4 below.

[Table 4]

Results on Co-Suspension of Fluticasone Propionate (FP) and Salmeterol Ginapoate (SX) of Example 5

Delivery dose uniformity through use was tested, and the individual delivery doses were all within ± 25% of the mean and the relative standard deviation (also referred to as “RSD”) was 6.1%. Visual observation of the co-suspension was performed in glass vials and no precipitation of activator particles was observed. The vial was allowed to stand for 24 hours without shaking. The suspension solidified slowly to form a homogeneous single cream layer.

Example  6

Formulations of a combination product of salmeterol gyapoate (SX) activator particles and fluticasone propionate (FP) activator particles in a co-suspension configuration are described. SX is present in the propellant as micronized crystalline particles. Co-suspend with spray dried suspended particles incorporating micronized FP in the material producing the suspended particles. To achieve this, FP crystals are suspended in the raw materials used to produce liquid suspension particles. The FP and SX used to form the activator particles and the suspension particles mentioned in this example were as described in Example 5, respectively.

FP-containing suspension particles were prepared as follows: An aqueous-fluorocarbon emulsion of 200 mL PFOB stabilized with phospholipids was prepared; 3.3 g of phospholipid (DSPC) and 0.8 g of micronized FP were dispersed and 0.3 g of calcium chloride dihydrate was dissolved in 100 ml of lukewarm water (70 ° C.) using a high shear mixer; During dispersion, 44 ml of PFOB was added slowly. The resulting crude emulsion was then further homogenized three times at 140 MPa using a high pressure homogenizer. Homogenization reduced the particle size of suspended FP crystals. The emulsion was spray dried in nitrogen using the following spray drying conditions: inlet temperature 95 ° C .; Outlet temperature 72 ° C .; Emulsion feed rate 2.4 ml / min; And total gas flow rate 525 L / min.

MDI was prepared by weighing micronized SX activator particles and FP-containing suspension particles of a target mass into a 19 ml volume fluorinated ethylene polymer (FEP) coated aluminum canister (Presspart, Blackburn, UK). The canister was press-sealed with a 63 μl valve (# BK 357, Bespak, King's Lynn, UK) and 10 mL of HFA 134a (1,1,1,2-tetrafluoroethane) by overpressure through the valve stem. (Ineos Fluor, Lyndhurst, UK). After injecting propellant, the canister was sonicated for 15 seconds and shaken with a wrist movement shaker for 30 minutes. The canister was mounted on a polypropylene actuator with a 0.3 mm orifice (# BK 636, Bespak, King's Lynn, UK). Aerosol performance was prepared according to USP 601 and evaluated immediately as described previously in Example 1. The results are reported in Table 5 below.

Table 5

Results on co-suspension of salmeterol ginapoate (SX) activator particles with fluticasone propionate-containing suspension particles.

Delivery dose uniformity in use was tested, and individual delivery doses were all within ± 25% of mean, with RSD of FP 9.0% and RSD of SX 13%. Visual observation of the co-suspension was performed in glass vials and no precipitation of activator particles was observed. The vial was allowed to settle for 24 hours without shaking. The suspension slowly aggregated to form a homogeneous single cream layer, showing no signs of separation of SX and suspended particles.

Example  7

Formulations of dual co-suspension compositions comprising budesonide activator particles and mometasone furoate activator particles are described. Budesonide (BD) and mometasone furoate (MF) were present in the propellant as micronized, crystalline particles and co-suspended with spray dried suspension particles.

BD, 16,17- (butylidenebis (oxy))-11,21-dihydroxy-, (11-β, 16-α) -pregna-1,4-diene-3,20-dione Micronized from manufacturer (AARTI, Mumbai, India) and used as active particles. The particle size distribution of budesonide was measured by laser diffraction. 50% by volume of the micronized particles showed an optical diameter of less than 1.9 μm, and 90% by volume showed an optical diameter of less than 4.3 μm.

MF, 9α, 21-dichloro-11β, 17-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione 17- (2-furoate) is a manufacturer (AARTI, Mumbai, India) It was taken as micronized from and used as activator particles. The particle size distribution of budesonide was measured by laser diffraction. 50% by volume of the micronized particles showed an optical diameter of less than 1.6 μm, and 90% by volume showed an optical diameter of less than 3.5 μm.

Suspension particles were prepared as follows: 500 mL of an emulsion of fluorocarbons in water of PFOB (perfluorooctyl bromide) stabilized by phospholipids was prepared; 18.7 g of phospholipid, DSPC (1,2-disteroyl-sn-glycero-3-phosphocholine) and 1.3 g of calcium chloride are homogenized in a high volume mixer at 400 mL of hot water (75 ° C.) ; 100 mL of PFOB was added slowly during homogenization. The resulting crude emulsion was then further homogenized using a high pressure homogenizer (Model C3, Avestin, Ottawa, CA) at a pressure of 170 MPa or less five times. The emulsion was spray dried using the following spray drying conditions: inlet temperature 95 ° C .; Outlet temperature 72 ° C .; Emulsion feed rate 2.4 ml / min; Total gas flow rate 498 L / min.

MDI was prepared by weighing the micronized activator particles and suspension particles of the target mass into 15 ml volumes of coated glass vials. The canister is press-sealed with a 63 μl valve (Valois, Les Vaudereuil, France) and 9.2 g of HFA 134a (1,1,1,2-tetrafluoroethane) by overpressure through the valve stem (Ineos Fluor, Lyndhurst , UK). After injecting propellant, the canister was sonicated for 15 seconds and shaken with a wrist movement shaker for 30 minutes. The suspension concentration was 0.8 mg / ml for BD activator particles, 1.1 mg / ml for MF activator particles and 6 mg / ml for suspension particles. The suspension particle ratio to the active agent particles was 7.5 for BD and 5.5 for MF. The pre-actuator target dose was 40 μg for BD and 55 μg for MF.

Visual observation of the co-suspended configuration showed no precipitation of the active agent particles. The vial was allowed to settle for 16 hours without shaking. No activator particles were visible at the bottom of the co-suspension vial. These results indicated that crystalline budesonide and mometasone furoate materials, which form different species of active agent particles, associate with the suspension particles and form a co-suspension of the composition disclosed herein. Since the sedimentation of the activator particles was successfully inhibited, the association between the activator particles and the suspended particles was strong enough to overcome the buoyancy.

Example  8

A double co-suspension composition was prepared using suspension particles comprising either mometasone furoate (MF) or budesonide (BD), and an MDI comprising the composition was prepared. The co-suspension composition comprised a combination of suspended particles comprising either MF or BD with crystalline glycopyrrolate (GP) and formoterol fumarate (FF) activator particles co-suspended. Each API served as micronized crystalline material.

Suspended particles comprising 50% (w / w) of either BD or MF were prepared as follows: 2.8 g of DSPC (1,2-distaroyl-sn) in 400 ml of hot water (75 ° C.) -Glycero-3-phosphocholine), and 56.6 g of PFOB was slowly added while high shear homogenization of the dispersion of 0.26 g of calcium chloride was carried out using a high shear mixer. Finely divided MF or BD (in a 1: 1 weight ratio to DSPC) was added to the resulting crude emulsion, using a high pressure homogenizer (Model C3, Avestin, Ottawa, CA) at a pressure of 170 MPa or less 3 to 5 times. Further homogenized. The emulsion was spray dried using the following spray drying conditions: inlet temperature 90-95 ° C .; Outlet temperature 95-72 ° C .; Emulsion feed rate 2-8 ml / min; Total dry nitrogen flow rate 525-850 L / min. The particle size distribution of the resulting powder was measured by laser diffraction, 50 vol% of the suspended particles were smaller than 1.8 μm, and the distribution width was 1.6 μm.

Canisters containing 50% (w / w) MF or BD containing suspended particles were filled with HFA 134a propellant and targeted at MF or MD 50 or 100 μg per operation, respectively. Their aerosol particle size distributions were measured according to the method described in Example 1 and the results are shown in Table 6. Similar series of canisters containing MF or BD containing suspension particles in combination with GP and FF activator particles were prepared. Sufficient undifferentiated GP and FF API materials were added to the canister in an amount sufficient to provide a target delivery dose of 36 μg / act and 6 μg / act for each of GP and FF. Additional placebo suspension particles (also referred to as “placebo” suspension particles) prepared as described herein but without any active agent were added until the co-suspension concentration was 5.5 mg / ml.

The aerosol particle size distribution provided by the co-suspension composition prepared according to this example was measured as described in Example 1 and the results are shown in Table 7 below. The mass median aerodynamic diameter of the corticosteroid in the single component suspension was equivalent to that obtained in a triple combination formulation prepared using two different active agent particles co-suspended with the BD or MF containing suspension particles. As in co-suspension compositions containing a combination of two different active agents, the triple co-suspension composition prepared according to the present specification had no combinatorial effect.

TABLE 6 Suspension MDI in HFA 134a propellant containing corticosteroid suspension particles. Aerosol Properties, Mass Aerodynamic Diameter and Fine Particle Fraction Measured by Drug-Specific Multistage Impact

TABLE 7 Triple combination suspension MDI in HFA 134a propellant comprising corticosteroid containing suspension particles (mometasone proate or budesonide), LAMA (glycopyrrolate) and LABA (promoterol fumarate). Aerosol properties, mass median aerodynamic diameter and fine particle fractions measured by drug specific multistage impact

Example  9

Triple co-suspension compositions according to the present disclosure were prepared, and MDI comprising the compositions was prepared. The composition included a combination of glycopyrrolate (GP), formoterol fumarate (FF), and mometasone furoate (MF) activator particles, each provided as a micronized crystalline API material.

Triple co-suspension MDI was prepared by semi-automated suspension filling. The triple co-suspension comprises three different active agent particles, namely MF (corticosteroid); It consisted of a combination of three microcrystalline active pharmaceutical ingredients forming GP (LAMA; and FF (LABA). These three different active particles were co-suspended with suspended particles in HFA 134a propellant. The following delivery dose targets were formulated: 50 μg MF per operation; 36 μg GP per operation; and 4.8 μg FF per operation.The monotherapy co-suspension containing only MF was prepared, with triple co-suspension. Therapeutic MF co-suspensions included MF activator particles co-suspended in propellant with the suspension particles described in this example and were formulated to provide a targeted delivery dose of 50 μg MF per operation.

Feedstock concentration 80 with 93.44% DSPC (1,2-distaroyl-sn-glycero-3-phosphocholine) and 6.56% anhydrous calcium chloride (corresponding to 2: 1 DSPC: CaCl ₂ moles / molar ratio) Suspended particles were prepared via a spray dried emulsion at mg / ml. During the emulsion preparation process, DSPC and CaCl ₂ were dispersed using a high shear mixer at 8000-10000 rpm in a vessel containing heated water (80 ± 3 ° C.) and PFOB was added slowly in the process. The emulsion was then treated five times in a high pressure homogenizer (10000-25000 psi). The emulsion was spray dried using a spray dryer equipped with a 0.42 "atomizer nozzle with an atomizer gas flow rate setpoint of 18 SCFM. The dry gas flow rate was 72 SCFM, the inlet temperature was 135 ° C, the outlet temperature was 70 ° C, and the emulsion flow rate was 58 ml. / Min.

For MDI preparation, the drug addition vessel (DAV) for suspension filling was prepared in the following manner: first half of the suspended particle amount was added, then the microcrystalline material was filled, and finally the other half of the suspended particles. Was added on top. Materials were added to the vessel in a humidity controlled environment of <10% RH. The DAV was then connected to a 4 L suspension vessel, flushed with HFA 134a propellant and mixed using a magnetic stir bar. The vessel internal temperature was maintained at 21-23 ° C. throughout the batch production. After recycling of the batch for 30 minutes, the canister was filled with the suspension mixture through a 50 μl EPDM valve. Sample canisters were randomly selected for full canister analysis to ensure correct formulation amount. The freshly prepared triple co-suspension MDI batch was then kept for 1 week before the initial product performance analysis. MDI with only mometasone furoate was prepared by filling the suspension in the same manner.

The primary particle size distribution of all microcrystalline APIs was measured by laser diffraction as described in Example 1 and the results are shown in Table 9. The aerodynamic particle size distribution and mass median aerodynamic diameter of all components in the operation of the suspension MDI were measured by drug specific multistage impact as described in Example 1 and shown in Table 9.

Table 9

Triple microcrystalline co-suspension MDI in HFA 134a propellant. Primary particle size distribution measured by laser diffraction (Sympatec)

Table 10

Triple co-suspension MDI in HFA 134a propellant comprising microcrystalline corticosteroids (mometasone furoate), LABA (formoterol fumarate) and LAMA (glycopyrrolate). Aerosol properties, mass median aerodynamic diameter and fine particle fractions are measured by drug specific multistage impact (NGI)

Delivery dose uniformity and aerosol performance achieved by the triple co-suspension prepared according to this example were evaluated according to the description set forth in Example 1. Figure 14 illustrates the DDUs of GP, FF and MF achieved from two canisters containing only MF prepared according to this example and two canisters containing MF, GP and FF. The DDU of MF delivered from the MF monotherapy construct was equivalent to that achieved by the triple co-suspension composition. The aerosol performance of the triple co-suspension composition prepared according to this example was evaluated in comparison to a formulation containing a combination of two active agents, FF and GP only. The aerodynamic particle size distributions of FF and GP were equivalent whether delivered from a composition comprising two or three active agents, as shown in FIGS. 15 and 16, respectively.

As with a co-suspension composition containing a combination of two different active agents, the triple co-suspension composition prepared according to this specification had no combinatorial effect.

Example  10

An exemplary triple co-suspension composition according to the present disclosure was prepared to prepare a quantitative aspirator comprising the composition. Triple co-suspensions are glycopyrrolate (GP) or tiotropium bromide (TB) in combination with formoterol fumarate (FF) and mometasone furoate (MF) activators, where API is used as the micronized crystalline material, respectively. ).

Two separate suspension MDI batches were prepared containing three active pharmaceutical ingredients (API), corticosteroids, LAMA and LABA. The API has been provided as microcrystalline material which acts as active particle particles co-suspended with suspended particles prepared as disclosed herein. The triple co-suspension composition prepared as described in this example was prepared by adding activator particles and suspension particles to the HFA 134a propellant.

The first triple co-suspension batch (triple GFM) was formulated with the following delivery dose targets: 40 μg MF per operation; 13 μg GP per operation; And 4.8 μg FF per operation. Activator particles were prepared using an emulsion consisting of 93.46% DSPC (1,2-dstearoyl-sn-glycero-3-phosphocholine) and 6.54% anhydrous calcium chloride spray dried at a feed concentration of 80 mg / ml Co-suspension with one suspension particle. The DSPC: CaCl ₂ molar ratio of the suspended particles was 2: 1. The active agent particles and suspending particles in the propellant were combined at a formulation target suspension particle concentration of 6 mg / ml. The primary particle size of the microcrystalline activator particles, measured by Sympatec laser diffraction measurement as described in Example 1, is presented in Table 11 below.

A second triple co-suspension batch (TFM) was prepared using a different LAMA API, anhydrous tiotropium bromide (TB) in place of GP. A second triple co-suspension was formulated with the following delivery dose targets: 50 μg MF per operation; 9 μg TB per operation; And 4.8 μg FF per operation. Suspension particles were prepared as described for triple GFM co-suspension and activator particles were co-suspended with suspension particles and targeted suspension particle concentrations of 6 mg / mL. The primary particle size of the microcrystalline activator particles determined by Sympatec laser diffraction measurement as described in Example 1 is shown in Table 12 below.

MDI was prepared using triple GFM and triple TFM co-suspension compositions, and the aerosol properties, fine particle fraction, and mass median aerodynamic diameter were measured as described in Example 1. Table 13 shows the MMAD and FPF performance for triple GFM and triple TFM, while the desired aerosol properties achieved by triple GFM and triple TFM co-suspension are shown in FIG. 17 (from triple GFM and triple TFM, respectively). Aerodynamic particle size distribution of GP and TB obtained).

Table 11

Triple GFM Primary Particle Size Distribution Measured by Laser Diffraction (Sympatec)

Table 12

Triple TFM Primary Particle Size Distribution Measured by Laser Diffraction (Sympatec)

Table 13

Triple GFM and Triple TFM Aerosol Properties, Mass Median Aerodynamic Diameter, and Fine Particle Fraction Measured by Drug-Specific Multistage Impact

Example  11

Exemplary double co-suspension compositions according to the present disclosure have been prepared, and MDI comprising the double co-suspension compositions have been prepared. The composition included a combination of glycopyrrolate (GP) and formoterol fumarate (FF), each provided as a micronized crystalline material having a particle size distribution as shown in Table 14. Microcrystalline GP and FF materials provided two activator particles, while suspended particles were prepared as described in Example 4. In preparing the double co-suspension described in this example, GP activator particles, FF activator particles, and suspension particles were combined in an HFA 134a propellant.

Appropriate amounts of GP and FF activator particles and suspension particles were first dispensed into a drug addition vessel (DAV) in a humidity control chamber (RH <5%) to prepare the double co-suspension described in this example. The DAV was then sealed under nitrogen atmosphere and connected to a suspension vessel containing 12 kg of HFA-134a. Thereafter, a slurry was formed by adding 0.5-1 kg of HFA-134a to the DAV, which was then removed from the suspension vessel and turned gently. The slurry was then returned to the suspension mixing vessel and diluted with additional HFA-134a to form the final suspension of the target concentration with gentle stirring with the impeller. The suspension was then recycled through the pump to the filling system for a minimum of time prior to the start of filling. Mixing and recycling were continued throughout the filling process. After the valve was placed on the MDI canister, the air was purged by a vacuum pressure welding process or by valve pressure welding after the HFA-134a purging process. The pressurized canister was then filled through a valve with the appropriate amount of suspension adjusted by the metering cylinder.

Table 14

Glycopyrrolate and Formoterol Fumarate Particle Size Distribution.

Appropriate amounts of micronized glycopyrrolate and formoterol fumarate crystals and suspended particles were first dispensed into a drug addition vessel (DAV) in a humidity control chamber (RH <5%) to prepare a suspension for pressure filling. In this example, suspension particle carriers were added by inserting GP and FF into three equal parts after the first and second additions, respectively. The DAV was then sealed under nitrogen atmosphere and connected to a suspension vessel containing 12 kg of HFA-134a. Thereafter, a slurry was formed by adding 0.5-1 kg of HFA-134a to the DAV, which was then removed from the suspension vessel and turned gently. The slurry was then returned to the suspension mixing vessel and diluted with additional HFA-134a to form the final suspension of the target concentration with gentle stirring with the impeller. The suspension was then recycled through the pump to the filling system for a minimum of time prior to the start of filling. Mixing and recycling were continued throughout the filling process. After the valve was placed on the canister, the air was purged by a vacuum pressure welding process or by valve pressure welding after the HFA-134a purging process. The pressurized canister was then filled through a valve with the appropriate amount of suspension adjusted by the metering cylinder.

MDIs containing the double co-suspension described in this example were prepared to contain two different doses of GP and FF. Specifically, the first double co-suspension composition is prepared to provide 18 μg GP per operation and 4.8 μg FF per operation (“low dose”), and the second double co-suspension composition is 36 μg per operation. Prepared to give 4.8 μg of FF per GP and run (“high dose”). In addition to the dual co-suspension compositions, monotherapy FF and GP co-suspension compositions were prepared. A monotherapy co-suspension composition was prepared as described for the dual co-suspension, except that it included only one active agent particle (either GP or FF). Monotherapy co-suspensions were formulated and monotherapy MDI was prepared to provide the following targeted delivery doses: 18 μg GP per operation, and 0.5, 1.0, 3.6 or 4.8 μg FF per operation. Compositions and MDIs that provide 0.5 μg FF and 1 μg FF per operation are referred to as “extremely low” dosages.

The drug specific aerodynamic size distribution achieved with MDI containing the co-suspension composition prepared according to this example was measured as described in Example 1. The proportionality of the aerodynamic size distribution of GP obtained from low and high dose double co-suspensions and the equivalence between dual and monotherapy co-suspensions were demonstrated in FIG. 18. Similarly, the proportionality of the aerodynamic size distribution of FF obtained from dual and monotherapy co-suspensions, including very low, low and high dose compositions, was demonstrated in FIG. 19.

Delivery dose uniformity of the ultralow dose FF monotherapy MDI was also measured as described in Example 1. DDUs, compositions and systems for 1 μg / operation and 0.5 μg / operation are shown in FIG. 20. The uniformity of delivery of the desired dose was achieved even at very low doses.

Example  12

The safety, efficacy and PK performance of the combination of co-suspension compositions described herein delivered via a quantitative aspirator (MDI) were evaluated in clinical trials. The combination co-suspension composition comprised both glycopyrrolate and formoterol fumarate. The clinical trial was a randomized, double-blind, customized, unbalanced, incomplete block, crossover, multi-center study performed in patients with mild to severe chronic obstructive pulmonary disease (COPD). Two different combination co-suspension compositions as described herein were compared with four activity comparative compositions that delivered only one of the two active agents included in the placebo and the combination composition.

The two combination co-suspension compositions administered in the clinical trial included both glycopyrrolate (GP) and formoterol fumarate (FF) active agents delivered in fixed combinations. Combination co-suspensions were generally prepared as described in Example 4 using GP and FF activator particles provided as micronized crystalline GP and FF materials, the suspension particles being spray dried particles containing DSPC and CaCl ₂ , and suspension medium Was prepared from HFA 134a. Combination co-suspension compositions were prepared for delivery to a patient via the MDI described herein and were adapted to facilitate administration of two different doses of the GP and FF active agents. The first co-suspension composition was formulated to deliver 36 μl GP and 4.8 μl FF to the patient each time the MDI was run and 72 μl GP and 9.6 μl FF to the patient twice daily (2 days per MDI operation). 2 doses). The first composition and treatment are also referred to in this example and the accompanying drawings as "GP / FF 72 / 9.6" and "GP / FF 72 / 9.6 treatment". The second co-suspension combination composition was formulated to deliver 18 μl GP and 4.8 μl FF to the patient every time the MDI was run, and 36 μl GP and 9.6 μl FF to the patient twice daily (1 operation with 2 operations of MDI). Twice daily). Such a second composition and treatment is also referred to as "GP / FF 36 / 9.6" and "GP / FF 36 / 9.6 treatment" in this example and the accompanying drawings.

GP / FF 72 / 9.6 and GP / FF 36 / 9.6 treatments were compared with five different active compositions comprising placebo and FF, GP or tiotropium as a single active agent. The first composition was the active control, Spiriva Handihaler (thiotropium bromide inhaled powder). Spiriva is a dry powder inhalant (DPI) product, administered to patients once a day, each DPI capsule containing 18 μl of tiotropium. The next composition, Foradil Aerolizer (formoterol fumarate inhaled powder), is also an active control. Foradil is also a DPI product, administered to patients twice daily, each DPI capsule containing a 12 μl dose of FF. The third composition is a co-suspension composition comprising only GP as the active agent. The monotherapy GP co-suspension composition (GP 36) was made for pulmonary delivery via MDI and administered twice daily, with 36 μl of GP delivered to the patient at each administration. The other two compositions are two different monotherapy co-suspension compositions comprising only FF as the active ingredient (FF 9.6 and FF 7.2). Monotherapy FF co-suspension compositions were prepared for pulmonary delivery via MDI and were administered twice daily, with 9.6 μl doses of FF (FF 9.6) or 7.2 μl doses of FF (FF 7.2) administered to the patient, respectively. Delivered. GP and FF monotherapy co-suspension compositions are formulated using undifferentiated crystalline GP or FF material as active particles, spray dried particles containing DSPC and CaCl ₂ as suspension particles, and HFA 134a as suspension medium. It was mad.

118 patients were randomly divided according to the study over a 7 day period and the study composition was administered over a 7 day period. On day 7 of treatment, the degree of FEV ₁ improvement in each patient was assessed over 12 hours after administration of each study composition, below the improvement curve of FEV _{1 over} baseline, provided by each study composition over a 12 hour period. The area (AUC _0-12 ) was calculated. The process of the seventh day AUC _{0 -12} (the seventh day) was used as a primary endpoint for the study. Secondary endpoints include peak changes in FEV ₁ after administration of each study composition on Days 1 and 7, with the lower FEV ₁ being prior to treatment on Day 7 of treatment in patients continuing for 7 days ( Morning low FEV ₁ ) and at safety assessment. Both GP / FF co-suspension compositions were safe and well tolerated.

The percentage of subjects who experienced a 12% improvement from baseline on day 1 (day ₁₎ at FEV ₁ and the percentage that experienced such improvement is shown in FIG. 21. As can be seen in FIG. 21, the cumulative response and onset rates provided by the GP / FF 72 / 9.6 and GP / FF 36 / 9.6 treatments were much improved over the cumulative response and onset rates provided by Spiriva. Compared to the control composition with only a single active agent, GP / FF 72 / 9.6 and GP / FF 36 / 9.6 treatments provided a greater change from baseline in FEV ₁ at day 7 (shown in FIGS. 11 and 24). .

GP / FF 72 / 9.6 and GP / FF 36 / 9.6 were both superior to all comparison groups for the primary endpoint. 25 is a GP / FF 72 / 9.6, GP / FF 36 / 9.6 The FEV ₁ AUC ₀ of the seventh day achieved by a _- represents an improvement as compared to _12, the respective active group compared with placebo. As can be seen in Figure 25, GP / FF 72 / 9.6 and GP / FF 36 / 9.6 is FEV ₁ AUC ₀ to the seventh day compared to the control group _composition was provided a much better improvement in the _12, GP / FF 72 / 9.6 and GP / FF 36 / 9.6 provided by the seventh day of FEV ₁ AUC _{0 - 12} is more improved in at least 80 ml was greater than that provided by each of the control group composition. FIG seventh day FEV ₁ AUC ₀ shown in 26 _- the difference in the ₁₂ jyeotneunde more pronounced, for example, GP 36, a seventh than FF 9.6, Spiriva, and Foradil comparators provided by the GP / FF 36 / 9.6 composition there was improvement in _{12 -} FEV ₁ AUC ₀ in the day.

As a reference point FEV ₁ AUC ₀ provided by the GP / FF 72 / 9.6 treatment _- by improvement of _12, 32 is that of all patients, moderate by GP / FF 36 / 9.6 and each of the control group COPD It presents the percent improvement in ₁₂ patients, and severe to very the seventh day given in patients with severe COPD in FEV ₁ AUC _0. The results presented in FIG. 32 indicate that the patient's responsiveness is consistent regardless of the severity of COPD.

GP / FF 72 / 9.6 and GP / FF 36 / 9.6 were also superior to all other comparison groups in the secondary end of the study. Vertex FEV ₁ presented in FIG. 27 Shows changes from baseline provided by each active study composition compared to placebo on days 1 and 7 of administration. As shown in FIG. 27, GP / FF 72 / 9.6 and GP / FF 36 / 9.6 provided superior vertex FEV ₁ on both the first and seventh days. FIG. 28 highlights the improvement in peak FEV ₁ as compared to Spiriva and Foradil provided by GP / FF 72 / 9.6 and GP / FF 36 / 9.6 on days 1 and 7. FIG. 29 shows the improvement at morning low FEV ₁ compared to the placebo provided by GP / FF 72 / 9.6, GP / FF 36 / 9.6, and the respective active comparison groups. As can be seen with reference to FIG. 29, the superior increase in FEV ₁ provided by the two combinatorial co-suspensions is better maintained over time, GP / FF 72 / 9.6 and GP / FF 36 / 9.6 The composition provides about a 50% improvement in the morning low FEV ₁ over the other activity comparisons.

30 shows an increase in pre-administration FEV ₁ on day 7 provided by GP / FF 72 / 9.6 and GP / FF 36 / 9.6 and on day 7 provided by GP 36, FF 9.6, Spiriva and Foradil comparison groups. The difference in increase in pre-administration FEV ₁ is shown. As can be readily seen with reference to FIG. 30, compared to the GP 36, FF 9.6, Spiriva and Foradil comparison groups, GP / FF 36 / 9.6 treatment showed a significantly greater improvement in pre-administration FEV ₁ on day 7. Provided.

In addition to the secondary endpoints specified for the study, respiratory capacity (IC) improvements were evaluated. GP / FF 72 / 9.6 and GP / FF 36 / 9.6 all provided a greater increase in IC compared to each comparison group on Days 1 and 7. For patients receiving GP / FF 72 / 9.6, GP / FF 36 / 9.6, and Spiriva, FIG. 31 shows peak improvement (day 1 peak) at IC experienced on day 1, of the test composition specified on day 7. Improvement in IC remaining in the patient prior to administration (day 7 preliminary), and peak improvement in IC experienced by the patient after administration of the specified composition (day 7 peak).

Claims (61)

A method of treating a lung disease or disorder in a patient comprising:
Suspension media comprising a pharmaceutically acceptable propellant;
Two or more active agents;
One or more active particles suitable for breathing; And
At least one suspending particles suitable for respiration, wherein the active particles and the suspending particles are associated in a suspension medium to form a co-suspension;
Providing a pharmaceutically acceptable co-suspension comprising; And
Administering the co-suspension to the patient as an aerosol suitable for breathing, wherein administering the co-suspension comprises delivering a therapeutically effective amount of two or more active agents to the patient. The method of claim 1, wherein the step of providing a pharmaceutically acceptable co-suspension comprises: short-acting beta agonists, long-acting and ultra-long-acting β ₂ adrenergic receptor agonists (LABA), corticosteroids, Anti-inflammatory agents, antitussives, bronchodilators, muscarin antagonists, and long-acting muscarin antagonists (LAMA) active agents, and two or more active agents selected from any pharmaceutically acceptable salts, esters, isomers, or solvates thereof. Providing a co-suspension. The method according to claim 2, wherein the lung disease or disorder is asthma, COPD, chronic bronchitis, emphysema, bronchiectasis, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergy, disturbed breathing, dyspnea syndrome, pulmonary hypertension, pulmonary vasoconstriction , Pulmonary inflammation associated with cystic fibrosis, and pulmonary occlusion associated with cystic fibrosis. 4. The method of claim 3, wherein providing a pharmaceutically acceptable co-suspension comprises: at least one of the at least one suspending particles comprises an active agent, wherein the at least two active agents are glycopyrrolate, dexypyrronium, tiotropium , LAMA activators selected from throsfum, aclidinium, and darotropium, bambuterol, clenbuterol, formoterol, salmeterol, caroterol, milbuterol, indacaterol, and salizinine- Or LABA activators selected from indole-containing and adamantyl-induced β ₂ agonists, and beclomethasone, budesonide, ciclesonide, flunisolidide, fluticasone, methyl-prednisolone, mometasone, Providing a co-suspension, selected from corticosteroid actives selected from prednisone and triamcinolone, and any pharmaceutically acceptable salts, esters, isomers or solvates thereof. Comprising the steps: 4. The method of claim 3, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising two or more different active agent particles, wherein each of the two or more active agent particles comprises a different active agent. And different active agents include LAMA activators selected from glycopyrrolate, dexypyrronium, tiotropium, throsfum, aclidinium, and darotropium, bambuterol, clenbuterol, formoterol, salmeterol , LABA activators selected from caroterol, milbuterol, indacaterol, and salinine- or indole-containing and adamantyl-induced β ₂ agonists, and beclomethasone, budesonide, ciclesonide , Corticosteroid actives selected from flunisolid, fluticasone, methyl-prednisolone, mometasone, prednisone and triamcinolone, and any pharmaceutically acceptable thereof Process selected from possible salts, esters, isomers or solvates. 6. The method of claim 5, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising three or more different active agent particles, wherein each of the three or more active agent particles comprises a different active agent. And different active agents include LAMA activators selected from glycopyrrolate, dexypyrronium, tiotropium, throsfum, aclidinium, and darotropium, bambuterol, clenbuterol, formoterol, salmeterol , LABA activators selected from caroterol, milbuterol, indacaterol, and salinine- or indole-containing and adamantyl-induced β ₂ agonists, and beclomethasone, budesonide, ciclesonide , Corticosteroid actives selected from flunisolid, fluticasone, methyl-prednisolone, mometasone, prednisone and triamcinolone, and any pharmaceutically acceptable thereof Process selected from possible salts, esters, isomers or solvates. 4. The method of claim 3, wherein providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising two or more different active agent particles, wherein each of the two or more active agent particles comprises a different active agent. Wherein at least one of the one or more suspending particles comprises a third active agent, and the different active agents are selected from glycopyrrolate, dexypyronium, tiotropium, throsfum, aclidinium, and darotropium From LAMA activators, bambuterol, clenbuterol, formoterol, salmeterol, caroterol, milbuterol, indacaterol, and salicidein- or indole- and adamantyl-induced β ₂ agonists Selected from LABA activators and beclomethasone, budesonide, ciclesonide, flunisolidide, fluticasone, methyl-prednisolone, mometasone, prednisone and triamcinolone It is selected from a corticosteroid active agent, and any pharmaceutically acceptable salt, ester, isomer or solvate. 4. The method of claim 3, wherein delivering a therapeutically effective amount of two or more active agents to the patient comprises a LAMA active agent selected from glycopyrrolate, dexipyronium, tiotropium, throsfum, aclidinium, and darotropium, And bambuterol, clenbuterol, formoterol, salmeterol, caroterol, milbuterol, indacaterol, and salicidenin- or indole-containing and adamantyl-induced β ₂ agonists Simultaneously delivering a LABA active agent, and a therapeutically effective amount of any pharmaceutically acceptable salt, ester, isomer, or solvate thereof. 4. The method of claim 3, wherein delivering a therapeutically effective amount of two or more active agents to the patient comprises a LAMA active agent selected from glycopyrrolate, dexipyronium, tiotropium, throsfum, aclidinium, and darotropium, And corticosteroid actives selected from beclomethasone, budesonide, ciclesonide, flunisolid, fluticasone, methyl-prednisolone, mometasone, prednisone and triamcinolone, and any pharmaceutically acceptable salts thereof Simultaneously delivering a therapeutically effective amount of an ester, isomer, or solvate. 4. The method of claim 3, wherein the step of delivering a therapeutically effective amount of two or more active agents to the patient comprises: snakebuterol, clenbuterol, formoterol, salmeterol, caroterol, milbuterol, indacaterol, and salizinin Or LABA activators selected from indole-containing and adamantyl-induced β ₂ agonists, and beclomethasone, budesonide, ciclesonide, flunisolidide, fluticasone, methyl-prednisolone, mometasone And simultaneously delivering a therapeutically effective amount of a corticosteroid active agent selected from prednisone and triamcinolone, and any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 4. The method of claim 3, wherein delivering a therapeutically effective amount of two or more active agents to the patient comprises a LAMA active agent selected from glycopyrrolate, dexipyronium, tiotropium, throsfum, aclidinium, and darotropium, LABA selected from Bambuterol, Clenbuterol, Formoterol, Salmeterol, Caroterol, Milveterol, Indacaterol, and Salicidenin- or indole-containing and Adamantyl-induced β ₂ agonists Active agents and corticosteroid active agents selected from beclomethasone, budesonide, ciclesonide, flunisolid, fluticasone, methyl-prednisolone, mometasone, prednisone and triamcinolone, and any pharmaceutically acceptable thereof Simultaneously delivering a therapeutically effective amount of a possible salt, ester, isomer or solvate. The method of claim 1, wherein administering the co-suspension to the patient results in a clinically significant increase in the FEV ₁ of the patient. The method of claim 12, wherein administering the co-suspension to the patient results in an increase of at least 150 mL of FEV ₁ in a period selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less. The method of claim 13, wherein administering the co-suspension to the patient results in an increase of at least 200 mL of FEV ₁ in a period selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less. The method of claim 14, wherein administering the co-suspension to the patient results in an increase of at least 250 mL of FEV ₁ in a period selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less. The method of claim 15, wherein administering the co-suspension to the patient results in an increase of at least 300 mL of FEV ₁ in a period selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less. The method of claim 16, wherein administering the co-suspension to the patient results in an increase of at least 350 mL of FEV ₁ in a period selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less. 18. The clinically significant increase in FEV ₁ achieved by administering a co-suspension to a patient according to any one of claims 1 to 17 wherein no more than 4 hours, no more than 6 hours, no more than 8 hours, no more than 10 hours. And remains clinically significant for a period selected from no more than 12 hours or less. 18. The method according to any one of claims 1 to 17, wherein administering the co-suspension to the patient at 50% or more of the patients at FEV ₁ for a period selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less and 2 hours. That results in an increase of more than 10%. 18. The method according to any one of claims 1 to 17, wherein administering the co-suspension to the patient at 60% or more of the patients at FEV ₁ for a period of time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less and 2 hours. That results in an increase of more than 10%. 18. The method according to any one of claims 1 to 17, wherein administering the co-suspension to the patient at 70% or more of the patients at FEV ₁ for a period of time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less and 2 hours. That results in an increase of more than 10%. 18. The method according to any one of claims 1 to 17, wherein administering the co-suspension to the patient at 80% or more of the patients at FEV ₁ for a period selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less and 2 hours. That results in an increase of more than 10%. Of claim 1 to claim 11, wherein a cavity patients increased from the above 200 ㎖ of FEV ₁ reference line to the patient by administering a suspension, or 12 from the reference line of the FEV _1, following the total increase of more than 150 ㎖ FEV ₁ The method that results in an increase of more than%. The method according to any one of claims 1 to 11, wherein the administration of the co-suspension to the patient results in at least 200 ml of FEV ₁ for a period selected from 1 hour or less, 1.5 hours or less, 2 hours or less and 2.5 hours or less. A method that results in an increase from baseline, or an increase of at least 12% from baseline in FEV ₁ accompanied by a total increase in FEV ₁ of at least 150 ml. The method of claim 24, wherein the increase from the over 200 ㎖ FEV ₁ reference line, or 150 ㎖ more FEV less than the more than 12% from the reference line of FEV ₁ to involve the entire increase in ₁ hour, 1.5 hours, 2 hours At least 50% of patients for a period of time selected from no more than 2.5 hours. 26. The method of claim 25, increases from the above 200 ㎖ FEV ₁ reference line, or 150 ㎖ more FEV less than the more than 12% from the reference line of FEV ₁ to involve the entire increase in ₁ hour, 1.5 hours, 2 hours At least 60% of the patients for a period of time selected from no more than 2.5 hours. The method of claim 24, wherein the increase from the over 200 ㎖ FEV ₁ reference line, or 150 ㎖ more FEV less than the more than 12% from the reference line of FEV ₁ to involve the entire increase in ₁ hour, 1.5 hours, 2 hours At least 70% of the patients for a period selected from no more than 2.5 hours. The method of claim 24, wherein the increase from the over 200 ㎖ FEV ₁ reference line, or 150 ㎖ more FEV less than the more than 12% from the reference line of FEV ₁ to involve the entire increase in ₁ hour, 1.5 hours, 2 hours At least 80% of the patients experience a period selected from no more than 2.5 hours. The method of claim 1, wherein administering the co-suspension to the patient results in a clinically significant increase in FEV ₁ in the patient, wherein the clinically significant increase in FEV ₁ is only one of the two or more active agents. A significant improvement over the increase provided by the composition delivering the The method of claim 29, wherein the significant improvement in FEV _{1 is} at least 70 ml. The method of claim 30, wherein the significant improvement in FEV _{1 is} at least 80 ml. 32. The method of claim 31, wherein the significant improvement in FEV _{1 is} at least 90 ml. 33. The method of any one of claims 30-32, wherein significant improvement is measured as improvement at peak FEV ₁ . 33. The method of any one of claims 30-32, wherein significant improvement is measured as improvement in FEV ₁ AUC _0-12 . 35. The method of any one of claims 1 to 34, wherein administering the co-suspension to the patient results in a clinically significant increase in inspiratory dose (IC). 36. The method of claim 35, wherein the clinically significant increase in IC is an increase of at least 100 ml. The method of claim 36, wherein the clinically significant increase in IC is an increase of at least 200 ml. 38. The method of claim 37, wherein the clinically significant increase in IC is an increase of at least 300 ml. The method of claim 38, wherein the clinically significant increase in IC is an increase of at least 350 ml. 40. The method of any one of claims 35-39, wherein a clinically significant increase in IC is achieved within 2 hours. 41. The method of any one of claims 35-40, wherein a clinically significant increase in IC is achieved within 1 hour. 42. The propellant according to any one of claims 1 to 41, wherein the suspension medium included in the co-suspension provided and administered as an aerosol suitable for breathing comprises a propellant selected from HFA propellant, PFC propellant and combinations thereof. How I practically do not contain additional ingredients. The suspension medium according to any one of claims 1 to 42, wherein the suspension medium included in the co-suspension provided and administered as an aerosol suitable for breathing consists essentially of a propellant selected from HFA propellants, PFC propellants and combinations thereof. , Wherein the propellant is substantially free of additional ingredients. 44. The method according to any one of claims 1 to 43, wherein at least two active agents included in the co-suspension provided and administered as aerosols suitable for breathing are glycopyrrolate, dexypyronium, tiotropium, tropium, LAMA activators selected from aclidinium, and darotropium, and any pharmaceutically acceptable salts, esters, isomers, or solvates thereof, and bambuterol, clenbuterol, formoterol, salmeterol, carmo Selected from terrols, milbuterols, indacaterols, and salicidenin- or indole-containing and adamantyl-induced β ₂ agonists and any pharmaceutically acceptable salts, esters, isomers or solvates thereof Lipid, phospholipids, nonionics are suitable for respiratory suspension particles selected from LABA activators and included in co-suspensions that are provided and administered as aerosols suitable for respiration. Claim, comprising an excipient selected from polymers, non-ionic block copolymer surfactants, non-ionic surfactants, biocompatible fluorinated surfactants, carbohydrates and one or more combinations thereof. 45. The method of claim 44, wherein the suspending particles suitable for breathing comprise perforated microstructures. 46. The method of claim 44 or 45, wherein the suspending particles suitable for respiration comprise DSPC and calcium chloride. 47. The method of any one of claims 42-46, wherein at least 50% by volume of the active agent particles included in the co-suspension provided and administered as an aerosol suitable for breathing has an optical diameter of 5 μm or less. 48. The method according to any one of claims 1 to 47, wherein the respirable suspending particles contained in the co-suspension provided and administered as an aerosol suitable for respiration are in the suspension medium about 1 mg / ml to about 15 mg /. At a concentration selected from ml, about 3 mg / ml to about 10 mg / ml, about 5 mg / ml to about 8 mg / ml and about 6 mg / ml. 49. The breathable suspension particles of any of claims 1-48, wherein the suspension particles are included in a co-suspension provided and administered as an aerosol suitable for breathing, from about 10 μm to about 500 nm, from about 5 μm to about 750 nm, MMAD selected from about 1 μm to about 3 μm. 50. The method of any of claims 1-49, wherein the respirable suspending particles contained in the co-suspension provided and administered as aerosols suitable for respiration are from about 0.2 μm to about 50 μm, from about 0.5 μm to about And a volume median optical diameter selected from 15 μm, about 1.5 μm to about 10 μm, about 2 μm to about 5 μm. 51. The method of any of claims 1-50, wherein the ratio of the total mass of suspended particles suitable for breathing to the total mass of one or more species of agent particles is greater than about 1.5, about 5 or less, about 10 or less, about 15 or less. , About 17 or less, about 20 or less, about 30 or less, about 40 or less, about 50 or less, about 60 or less, about 75 or less, about 100 or less, about 150 or less, and about 200 or less. The method of any one of claims 1-51, wherein the ratio of the total mass of the one or more species of suspended particles to the total mass of the one or more species of active particles is between about 3: 1 and about 15: 1 and between about 2: 1 and 55. Method selected from 8: 1. 53. The breathable suspension particles according to any one of claims 1 to 52, which are included in the co-suspension provided and administered as an aerosol suitable for breathing, at least 1 g, at least 10 g, at least 50 g and 100. A process that remains associated with an active agent particle even when buoyancy amplified by centrifugation is applied at an acceleration selected from an acceleration of at least g. 55. The active agent of any one of claims 1-53 wherein the active agent particles contained in the co-suspension provided and administered as an aerosol suitable for breathing comprise the first and second active agent particles, Activator particles of comprises glycopyrrolate and any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the second type of activator particles comprises formoterol and any pharmaceutically acceptable salts, esters thereof , Isomers or solvates. 55. The method of claim 54, wherein the first type of active agent particle comprises crystalline glycopyrrolate and the second type of active agent particle comprises crystalline formoterol. 55. The HFA propellant according to claim 54, wherein the co-suspension provided as an aerosol suitable for breathing and administered is substantially free of additional ingredients, two active agents provided as active particles of the first and second species, and phospholipid excipients. Consisting essentially of breathable suspension particles formed from the two active agents provided as the first and second types of active particles, and the first type of active particles are crystalline glycopyrrolate and any pharmaceutically acceptable thereof. Possible salts, esters, isomers or solvates, and wherein the second type of active particles comprise formoterol and any pharmaceutically acceptable salts, esters, isomers or solvates thereof. The method of any one of claims 1-56, wherein the pharmaceutically acceptable co-suspension is provided and administered from MDI. 58. The method of any one of claims 44 to 57, wherein administering the co-suspension as an aerosol suitable for breathing to the patient comprises administering the co-suspension to the patient no more than twice a day. The method comprises delivering up to 150 μg LAMA activator and up to 12 μg LABA activator. 59. The method of any one of claims 44 to 58, wherein administering the co-suspension as an aerosol suitable for breathing to the patient comprises administering the co-suspension to the patient no more than twice a day, each administration The method comprises delivering up to 100 μg LAMA activator and up to 12 μg LABA activator. 60. The method of any one of claims 44 to 59, wherein administering the co-suspension as an aerosol suitable for breathing to the patient comprises administering the co-suspension to the patient no more than twice a day, The method comprises delivering up to 80 μg LAMA activator and up to 12 μg LABA activator. 61. The method of any one of claims 44 to 60, wherein administering the co-suspension as an aerosol suitable for breathing to the patient comprises administering the co-suspension to the patient no more than twice a day. The method comprises delivering 50 μg or less of the LAMA activator and 12 μg or less of the LABA activator.

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