JP2014518871A - Compositions, methods and systems for delivering two or more active agents to the respiratory tract - Google Patents

Abstract

Compositions, methods and systems are provided for pulmonary or nasal delivery of two or more active agents via a metered dose inhaler. In one embodiment, the composition comprises a suspending medium, active agent particles and suspending particles, wherein the active agent particles and suspending particles form a co-suspension within the suspending medium.
[Selection figure] None

Description

The present disclosure relates generally to compositions, methods and systems for delivering two or more active agents to the respiratory tract. In certain aspects, the present disclosure relates to compositions, methods and systems for respiratory delivery of two or more active agents, and in particular, at least one of the active agents is a long-acting long-acting antagonist. muscarinic antagonist: LAMA), long-acting beta _2-adrenergic agonist _{(long-acrting β 2 adrenergic agonist} : LABA), and is selected from corticosteroid active agent.

  A targeted drug delivery method of delivering an active agent to the site of action is often desirable. For example, targeted delivery of active agents can reduce adverse side effects, reduce dosage requirements, and reduce treatment costs. For respiratory delivery, an inhaler is a well-known device for administering an active agent to a subject's respiratory tract, and currently several different inhaler systems are commercially available. Common three inhaler systems include dry powder inhalers, nebulizers and metered dose inhalers (MDI).

  MDI can be used to deliver the drug in solubilized form or as a suspension. Typically, when the MDI is activated, the MDI ejects aerosolized droplets containing the active agent into the airway using a relatively high vapor pressure propellant. A dry powder inhaler generally introduces a drug in dry powder form into the respiratory tract, depending on the patient's inspiratory effort. On the other hand, the nebulizer forms a drug aerosol to be inhaled by imparting energy to the solution or suspension.

  MDI is an active delivery device that utilizes the pressure generated by a propellant. Traditionally, chlorofluorocarbons (CFCs) have been used as MDI-based propellants because CFCs are less toxic and have the desired vapor pressure and compatibility for the production of stable suspensions. However, traditional CFC propellants are understood to have a negative impact on the environment, which leads to the development of alternative propellants (such as perfluorinated compounds (PFC) and hydrofluoroalkanes (HFA)) that are considered more environmentally friendly. I came.

  The active agent to be delivered by suspension MDI is typically supplied as a fine particle dispersed within a propellant or a combination of two or more propellants (ie, a propellant “system”). Is done. In order to form the microparticles, the active agent is typically micronized. Active agent microparticles suspended in a propellant or propellant system tend to rapidly aggregate or coagulate. This is especially true for active agents present in micronized form. Aggregation or coagulation of these microparticles may then complicate delivery of the active agent. For example, agglomeration or coagulation may cause mechanical failure that may occur due to blockage of the valve opening of the aerosol container. Inadvertent aggregation or coagulation of drug particles can also lead to rapid settling or creaming of the drug particles, and such behavior can cause inconsistent dose delivery, especially very powerful low dose drugs It is considered troublesome. Another problem with such suspension MDI formulations relates to drug growth during storage, which reduces the aerosol properties and delivery dose uniformity of MDI over time. More recently, an approach as disclosed in US Pat. No. 6,964,759 (Patent Document 1) has been proposed for an MDI preparation containing an anticholinergic agent.

  One approach to improve aerosol performance in dry powder inhalers has been to incorporate fine particle carrier particles (such as lactose). The use of such fine excipients has not been studied as much for MDI. A recent report by Young et al., “The influence of micronized particulates on the aerosolization properties of selected metered dose inhalers”, Aerosol Science 40, pp. 324-337 (2009) (Non-Patent Document 1), describes such a particulate carrier in MDI. This suggests that aerosol performance actually decreases.

  In conventional CFC systems, when the active agent present in the MDI formulation is suspended in a propellant or propellant system, to minimize or prevent aggregation problems and maintain a substantially uniform dispersion, Often surfactants are used to coat the surface of the active agent. The use of surfactants in this manner is sometimes referred to as “stabilizing” the suspension. However, many surfactants that are soluble and effective in CFC systems are not effective in HFA and PFC propellant systems. This is because such surfactants exhibit different solubility characteristics in non-CFC propellants.

U.S. Patent No. 6,964,759

Young et al., `` The influence of micronized particulates on the aerosolization properties of selected metered dose inhalers '', Aerosol Science 40, 324-337 (2009)

The present disclosure provides compositions, methods and systems for respiratory delivery of two or more active agents. In particular embodiments, the present disclosure encompasses pharmaceutical compositions, systems and methods for respiratory delivery of two or more active agents by MDI, and in certain embodiments, at least one of the active agents. Is selected from long acting muscarinic antagonists (LAMA), long acting β ₂ adrenergic agonists (LABA) and corticosteroid activators. The compositions described herein can be formulated for pulmonary or nasal delivery by MDI. The methods described herein include methods for stabilizing a formulation comprising two or more active agents for respiratory delivery, as well as two or more active agents for treating pulmonary diseases or disorders by MDI. A method of pulmonary delivery. Further described herein are MDI systems for delivering two or more active agents, as well as methods for making the systems.

  Difficult to formulate a pharmaceutical composition that incorporates two or more active agents due to unpredictable or unexpected interactions between the active agents, or formulation changes resulting from the incorporation of various active agents There are many things. Such interactions are commonly known as “combination effects” and in suspension formulations delivered from MDI, for example: aerosols provided by the formulation and particle size distribution size distribution); delivery dose uniformity for one or more of the active agents; deliverability or absorbability of one or more of the active agents; or dose proportionality observed for one or more of the active agents In one or more of the dose proportionalities, due to deviations from the similarity between a formulation containing a single active agent and a formulation containing a combination of two or more active agents, The effect of the combination may become apparent.

  In a specific embodiment, the co-suspension compositions described herein avoid the combination effects associated with combination formulations. For the purposes of this description, the composition avoids the effects of the combination, where the aerosol properties, particle size distribution characteristics and delivery dose uniformity achieved by the combination formulation are only for selected active agents. It does not deviate from the aerosol properties, particle size distribution characteristics and delivery dose uniformity achieved by comparable formulations in which the active agent is the selective active agent. Selection of the targeted dose delivered from the combination formulation from the plasma concentration over time achieved when the active agent selected at the same dose is delivered from a similar formulation where the only active agent is its selective active agent In some embodiments, where the plasma concentration of the active agent does not deviate over time, it has been demonstrated that there is no combined effect on the selected active agent.

  As used herein, the phrase “do not deviate or does not deviate” means that the performance achieved by the combination formulation for a given parameter is a combination thereof. It shows ± 20% of the performance achieved by a similar formulation containing only one of the active agents contained in the formulation. In certain embodiments, the performance achieved by the combination formulation is not different from the performance achieved by a similar formulation comprising only one of the active agents included in the combination. For example, a co-suspension as described herein comprising two or more active agents is the aerosol properties, particle size distribution achieved by the combined co-suspension for each such active agent at a given dose. Of aerosol characteristics, particle size distribution characteristics, delivery dose uniformity and plasma concentration over time, wherein one or more of the following characteristics, delivery dose uniformity and plasma concentration over time are achieved by similar formulations containing only a single active agent When within ± 20%, it is considered not to show the effect of the combination. In some embodiments, for each active agent at a given dose, the aerosol properties, particle size distribution characteristics, delivery dose uniformity, and plasma concentration over time achieved by the combination co-suspension compositions described herein. One or more of them are within ± 15% of the aerosol properties, particle size distribution characteristics, delivery dose uniformity and plasma concentrations over time achieved by similar formulations containing only a single active agent. In yet another aspect, for each active agent at a given dose, the aerosol properties, particle size distribution characteristics, delivery dose uniformity and plasma over time achieved by the combination co-suspension compositions described herein One or more of the concentrations are within ± 10% of the aerosol properties, particle size distribution characteristics, delivery dose uniformity and plasma concentration over time achieved by similar formulations containing only a single active agent. In certain embodiments, for each active agent at a given dose, the combination co-suspension compositions described herein provide the following formulation aerosol properties, particle size distribution characteristics, delivery dose uniformity and One or more of the plasma concentrations over time does not differ from similar formulations containing only one of the active agents included in the combination.

  The combination of two or more active agents included in the compositions provided herein can provide an advantage over a pharmaceutical formulation that, in some embodiments, includes only a single active agent. For example, when delivering a combination of two or more active agents at the same time, the therapeutically effective dose of both active agents may be relatively less than when either of the combined active agents is delivered alone. , Thereby avoiding or reducing possible side effects. Furthermore, a combination of two or more active agents may have a faster onset of therapeutic benefit or a longer duration than can be achieved by delivering one of the combined active agents alone. Can be achieved.

  In certain aspects, the methods described herein include methods for treating pulmonary diseases or disorders that are amenable to treatment by respiratory delivery of the co-suspension compositions described herein. For example, the compositions, methods and systems described herein can be used to treat inflammatory or obstructive pulmonary diseases or conditions. In certain embodiments, the compositions, methods and systems described herein are used to reduce asthma, chronic obstructive pulmonary disease (COPD), exacerbated airway hyperresponsiveness resulting from other medications, allergic rhinitis , Sinusitis, pulmonary vasoconstriction, inflammation, allergies, respiratory disorders, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, and for example, LAMA, LABA, corticosteroids or other active agents described herein Suffers from any other respiratory disease, symptom, trait, genotype or phenotype that can respond to administration (whether alone or in combination with other therapies) Can treat patients. In certain aspects, the compositions, systems and methods described herein can be used to treat lung inflammation and obstruction associated with cystic fibrosis. As used herein, the terms “COPD” and “chronic obstructive lung disease” refer to chronic obstructive lung disease (COLD), chronic obstructive airway disease (COAD). Including chronic airflow limitation (CAL) and chronic obstructive respiratory disease (CORD), including chronic bronchitis, bronchiectasis and emphysema. As used herein, the term “asthma” refers to all asthma, regardless of type or origin, and includes the following: endogenous (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, Includes moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection. Asthma should also be understood as a comprehensive infant wheezing syndrome.

When administered to a patient suffering from pulmonary disease, embodiments of the co-suspension composition described herein provide pulmonary function or vital capacity when compared to compositions that deliver only a single active agent. Provide a significant increase in one or more of the following measures. In certain such embodiments, delivery of a co-suspension composition described herein comprising two or more active agents results in FEV ₁ and deep breaths for compositions comprising only a single active agent. There is a significant increase in one or both of the quantities (IC).

  It will be readily appreciated that aspects as generally described herein are exemplary. The following more detailed description of various aspects is not intended to limit the scope of the present disclosure, but is merely representative of various aspects. Accordingly, the details recited herein may independently include patentable subject matter. Furthermore, the order of the method steps or acts described in connection with the embodiments disclosed herein can be changed by those skilled in the art without departing from the scope of the disclosure. In other words, as long as a specific order of steps or actions is not necessary to correctly operate the aspect, the order or use of specific steps or actions can be changed.

FIG. 1 is a graph showing the delivered dose uniformity of a co-suspension formulation comprising glycopyrrolate and formoterol fumarate prepared according to the present description. FIG. 2 is a graph showing the delivery dose ratio of the co-suspension formulation of FIG. FIG. 3 is a graph showing the delivery dose uniformity of a second co-suspension formulation made in accordance with the present description. FIG. 4 is a graph showing the delivery dose ratio of the second co-suspension formulation of FIG. FIG. 5 is a graph showing the delivered dose uniformity of glycopyrrolate and formoterol fumarate in a co-suspension formulation made according to the description of the invention when stored under various conditions as described. FIG. 6 is a graph showing the particle size distribution of an exemplary co-suspension formulation made according to the description of the invention when stored under various conditions as described. FIG. 7 is a graph showing the particle size distribution achieved by an exemplary co-suspension comprising a combination of glycopyrrolate and formoterol fumarate when stored under conditions as described. FIG. 8 shows an exemplary co-suspension comprising a combination of glycopyrrolate and formoterol fumarate compared to a particle size distribution achieved by a formulation comprising either glycopyrrolate or formoterol fumarate alone. 2 is a graph showing the particle size distribution achieved. FIG. 9 is a graph showing serum glycopyrrolate and formoterol concentration levels over time achieved after delivery of an exemplary co-suspension comprising glycopyrrolate prepared according to the present description and formoterol fumarate. The serum concentration time profile of glycopyrrolate and formoterol fumarate delivered from this exemplary combination formulation is compared to the profile achieved by a composition containing and delivering glycopyrrolate or formoterol fumarate alone. FIG. 10 shows a two-part co-suspension containing microcrystalline formoterol fumarate and glycopyrrolate activator particles compared to a co-suspension containing only crystalline formoterol fumarate prepared according to the present description ( It is a graph which shows the formoterol particle size distribution achieved by dual co-suspension). FIG. 11 is a graph showing the glycopyrrolate particle size distribution achieved with a two-component co-suspension produced according to the present description. This includes microcrystalline glycopyrrolate activator particles, microcrystalline formoterol fumarate activator particles with two different particle size distributions (labeled “fine” and “coarse”), or spray dried formoterol fumarate. Was included. FIG. 12 is a graph showing the formoterol fumarate particle size distribution achieved with the second two-component co-suspension produced according to the present description. This contained microcrystalline formoterol fumarate and microcrystalline glycopyrrolate activator as compared to a co-suspension containing microcrystalline glycopyrrolate activator particles and spray dried formoterol fumarate particles. FIG. 13 is a graph showing the delivery dose uniformity of glycopyrrolate and formoterol fumarate in an exemplary two-part co-suspension formulation made according to the present description. FIG. 14 shows the delivery dose uniformity of each active agent contained in an exemplary triple co-suspension composition. This included microcrystalline glycopyrrolate, formoterol fumarate and mometasone furoate active particles. FIG. 15 is achieved with a three-part co-suspension prepared according to the present description (containing microcrystalline glycopyrrolate activator particles, formoterol fumarate activator particles and mometasone furoate activator particles). FIG. 5 is a graph showing the aerodynamic particle size distribution of formoterol fumarate compared to that achieved with a two-part co-suspension (which contained glycopyrrolate and formoterol fumarate). FIG. 16 is achieved with a three-part co-suspension prepared according to the present description, which contained microcrystalline glycopyrrolate activator particles, formoterol fumarate activator particles and mometasone furoate activator particles. FIG. 5 is a graph showing the aerodynamic particle size distribution of glycopyrrolate compared to that achieved with a two-component co-suspension (which contained glycopyrrolate and formoterol fumarate). FIG. 17 shows a three-part co-suspension prepared according to the present description (either glycopyrrolate activator particles or tiotropium bromide activator particles plus microformer activator formoterol fumarate and mometasone furoate). Is a graph showing the aerodynamic particle size distribution of glycopyrrolate and tiotropium bromide achieved by FIG. 18 is a graph showing the aerodynamic size distribution of glycopyrrolate achieved with two two-component co-suspensions prepared according to the present description and one single-component co-suspension. 2 shows dose proportionality between two two-component co-suspensions, as well as equivalence between two-component and single-component co-suspensions. FIG. 19 is a graph showing the aerodynamic size distribution of formoterol fumarate achieved with two two-component co-suspensions prepared according to the present description and two single-component co-suspensions. Dose proportionality between two two-component co-suspensions and two single-component co-suspensions, and between two-component co-suspensions and single-component co-suspensions Indicates equivalence. FIG. 20 is a graph showing dose delivery uniformity of an ultra-low dose formoterol fumarate single component co-suspension made according to the present description. FIG. 21 shows two different co-suspensions delivering a single active agent (one delivering only glycopyrrolate—GP36 and the second delivering only tiotropium bromide—Spiriva) Cumulative over time on day 1 applying two treatments using the combination co-suspension compositions described herein (GP / FF 72 / 9.6 and GP / FF 36 / 9.6) It is a figure which shows a response. These compositions were administered to patients as part of the clinical study described in Example 12. Specifically, this graph shows the percentage of patients achieving > 12% improvement with FEV ₁ and the time at which the percentage was achieved. 22-24 are from the FEV ₁ AUC _0-12 baseline on treatment day 7 (Day 7) for various study compositions administered to patients as part of the clinical study described in Example 12. It is a graph which shows the average change (mean change). Two treatments using the combination co-suspension compositions described herein (GP / FF 72 / 9.6 and GP / FF 36 / 9.6) consist of various active compositions that deliver placebo and a single active agent. Products (one delivering only glycopyrrolate-GP36, the second delivering only tiotropium bromide-Spiriva, and the third delivering only formoterol fumarate-FF 7.2, FF 9.6, and Compare with Foradil). FIG. 23 shows the mean from the FEV ₁ AUC _0-12 baseline on treatment day 7 (Day 7) for various study compositions administered to patients as part of the clinical study described in Example 12. It is a graph which shows a change (mean change). FIG. 24 shows the mean from the FEV ₁ AUC _0-12 baseline on treatment day 7 (Day 7) for various study compositions administered to patients as part of the clinical study described in Example 12. It is a graph which shows a change (mean change). FIG. 25 is a graph showing FEV ₁ AUC _0-12 on day 7 for each active study composition administered to patients as part of the clinical trial described in Example 12. Improvements in FEV ₁ AUC _0-12 provided by each active study composition against placebo are shown. FIG. 26 is a graph showing the difference between FEV ₁ AUC _0-12 achieved by GP / FF 36 / 9.6 treatment on day 7 for GP 36, FF 9.6, Spiriva and Foradil activity comparators. As readily understood with reference to FIG. 26, GP / FF 36 / 9.6 treatment provided significantly better improvements in FEV ₁ AUC _0-12 . FIG. 27 is a graph showing peak FEV ₁ on treatment day 1 (day 1) and day 7 achieved with various study compositions administered to patients as part of the clinical study described in Example 12. It is. The indicated peak FEV ₁ represents the peak change in FEV ₁ from baseline provided by each active study composition for the placebo on the indicated day. FIG. 28 is a graph showing the difference between peak FEV ₁ achieved by GP / FF 36 / 9.6 on day 1 and day 7 for Spiriva and Foradil activity comparators. As is readily understood by referring to FIG. 28, GP / FF 36 / 9.6 treatment provided a significantly better improvement in peak FEV ₁ compared to the active comparator. FIG. 29 is a graph showing the improvement in Morning Trough FEV ₁ achieved by various study compositions administered to patients as part of the clinical study described in Example 12. This graph shows the improvement in Morning Trough FEV ₁ value provided by each active study composition versus placebo. FIG. 30 shows two treatments using different single active agent comparators and the combination co-suspension compositions described herein (GP / FF 72 / 9.6 and GP / FF 36 / 9.6) compared to each other. 12 is a graph showing the difference between the increase in pre-dose FEV ₁ on day 7 of the clinical study described in Example 12, provided by FIG. As readily understood with reference to FIG. 30, GP / FF 72 / 9.6 and GP / FF 36 / 9.6 treatments were significantly better at pre-dose FEV ₁ compared to a single active agent comparator Provided significant improvements, but there was no significant difference between each other. FIG. 31 uses a combination co-suspension composition (GP / FF 72 / 9.6 and GP / FF 36 / 9.6) and a Spiriva active comparator composition administered as part of the clinical trial described in Example 12. FIG. 6 is a graph showing the peak at day 1 and day 7 in deep expiratory volume (IC) versus placebo and the pre-dose improvement at day 7 provided by the two treatments. FIG. 32 is a graph showing the consistent patient response achieved in the clinical study described in Example 12, regardless of the severity of the chronic obstructive pulmonary disease that the patient is afflicted with.

I. Definitions Unless defined otherwise, technical terms used herein have their ordinary meaning as understood in the art. For clarity, the following terms are specifically defined.

  The term “active agent” as used herein refers to any drug, drug, compound, composition or other substance that can be used or administered to a human or animal for any purpose, such as a therapeutic agent. , Pharmaceuticals, pharmacological agents, diagnostic agents, cosmetic and prophylactic agents and immunomodulators. The term “active agent” is interchangeable with the terms “drug”, “pharmaeutical”, “mediament”, “drug substance” or “therapeutic”. Can be used. As used herein, an “active agent” may include natural products or homeopathic products that are not generally considered therapeutic agents.

  The terms `` associate '', `` associate with '' or `` association '' refer to a chemical that is in close proximity to a surface, such as the surface of another chemical, composition or structure, Refers to an interaction or relationship between compositions or structures. Associations include, for example, adsorption, adhesion, covalent bonding, hydrogen bonding, ionic bonding and electrostatic attraction, Lifshitz van der Waals interactions and polar interactions. The term “adhere” or “adhesion” is a form of association and is a general term for all forces that tend to attract particles or masses to a surface. used. “Gluing” also causes the particles to come into contact with each other so that there is virtually no visible separation between the particles due to the different buoyancy of the particles in the propellant under normal conditions. Let's keep that state. In one aspect, particles that adhere to or bind to a surface are encompassed by the term “adhere”. Examples of normal conditions include storage at room temperature or under acceleration force due to gravity. As described herein, the active agent particles can associate with the suspended particles to form a co-suspension. In that case, due to the difference in buoyancy within the propellant, there is virtually no visible separation between the suspended particles and the active agent particles or their coagulum.

  “Suspended particles” refers to a substance or combination of substances that is acceptable for respiratory delivery and that acts as a vehicle for the active agent particles. The suspended particles interact with the active agent particles to facilitate repeatable administration, delivery or transport of the active agent to the target site of delivery, ie, the respiratory tract. The suspended particles described herein can be dispersed in a suspending medium, such as a propellant or propellant system, in any shape, size suitable for achieving the desired suspension stability or active agent delivery capability. Or it can be configured according to surface features. Exemplary suspended particles exhibit a particle size that facilitates respiratory delivery of the active agent and are suitable for formulation and delivery of stabilized suspensions as described herein. Examples thereof include particles having a physical configuration.

  The term “co-suspension” refers to a suspension having two or more particles of different composition in a suspending medium. At this time, one type of particles is at least partially associated with one or more of the other types of particles. This association causes a noticeable change in one or more characteristics of at least one of the individual particle species suspended in the suspending medium. Characteristics modified by this association include, for example, the rate of aggregation or coagulation, the rate and nature of separation, ie sedimentation or creaming, the density of the cream or sedimentation layer, adhesion to the container wall, adhesion to valve components, and One or more of the speed and level of dispersion during agitation can be mentioned.

  Exemplary methods for evaluating whether a co-suspension is present include the following. If the density bottle density of one particle type is higher than the propellant and the density bottle density of another particle type is lower than the propellant, the presence of the co-suspension can be confirmed using visual observation of creaming or sedimentation behavior. The term “pycnometric density” refers to the density of the material comprising the particles, excluding voids within the particles. In one embodiment, the material can be formulated or transferred to a clear vial, generally a glass vial, for visual observation. After the initial stirring, the vial is allowed to stand for a time sufficient to form a sedimented or cream layer, typically 24 hours. A co-suspension is present when the sedimented or cream layer is observed to be completely or mostly uniform single layer. The term “co-suspension” means that most of at least two particle types associate with each other, but separation may be observed in some (ie, less than most) of at least two particle types. Includes partial co-suspension.

  Exemplary co-suspension tests can be conducted at various propellant temperatures to enhance the sedimentation or creaming behavior of particle species having a density close to the propellant density at room temperature. If different particle types have the same separation properties, i.e. all settled or all creamed, the presence of the co-suspension is responsible for other characteristics of the suspension, e.g. aggregation or coagulation rate, separation rate, cream layer or sedimented layer. Measure the density, adhesion to the vessel wall, adhesion to the valve components, and the rate and level of dispersion during agitation, and compare the measurements to the respective characteristics of the individual suspended particle types as well. Can be determined. These characteristics can be measured using various analytical methods known to those skilled in the art.

  For compositions that contain or provide respirable aggregates, particles, droplets, such as the compositions described herein, the term “fine particle dose” or “FPD” refers to a dose in the form of either a nominal or metered dose, either in the total mass or fraction, within the breathable range. The dose within the breathable range is filtered from stage 3 with the Next Generation Impactor operating at a flow rate of 30 l / min, ie the dose that accumulates beyond the cascade impactor's throat stage. Measure in vitro to be the total delivered dose.

  For compositions that contain or provide respirable aggregates, particles, droplets, such as the compositions described herein, the term “fine particle fraction” or “FPF” is delivered. The ratio of the dose to the delivery dose within the breathable range, i.e. the amount leaving the actuator of a delivery device such as MDI. The amount of delivery material within the respirable range is the amount of material that accumulates beyond the throat stage of the cascade impactor, for example, the material delivered by the filter from stage 3 in the Next Generation Impactor operated at a flow rate of 30 l / min. Measured in vitro as the sum of

  As used herein, the term “inhibits” refers to a tendency for a phenomenon, sign or symptom to occur, or a measurable decrease in the extent to which the phenomenon, sign or symptom occurs. The term “inhibit” or any form thereof is used in its broadest sense to minimize, prevent, reduce, suppress, suppress, suppress, inhibit, limit Includes delaying progress.

  As used herein, “mass median aerodynamic diameter” or “MMAD” consists of particles below which 50% of the mass of the aerosol has an aerodynamic diameter less than MMAD. , Refers to the aerodynamic diameter of the aerosol, and MMAD is calculated according to United States Pharmacopoeia (USP) monograph 601.

  As referred to herein, the term “optical diameter” refers to Fraunhofer diffraction using a laser diffraction particle size analyzer (eg, Sympatec GmbH, Clauthal-Zelerfeld, Germany) equipped with a dry powder dispenser. The particle diameter when measured by mode is shown.

  The term solution mediated transformation means that a more soluble solid material (i.e. a particle with a small radius of curvature (driving force towards Ostwald ripening) or an amorphous material) dissolves and saturates it. It refers to the phenomenon of recrystallization to a more stable crystal form that can coexist in equilibrium with the propellant solution.

  “Patient” refers to an animal in which a combination of active agents described herein will have a therapeutic effect. In one aspect, the patient is a human.

  A “perforated microstructure” allows the surrounding suspension medium to penetrate, fill or fill the microstructure, such as materials and preparations described in US Pat. No. 6,309,623 to Weers et al. Refers to a suspended particle comprising a structural matrix that defines, includes or includes voids, pores, defects, cavities, spaces, interstitial spaces, openings, pores or pores. The basic form of the perforated microstructure is generally not critical and any overall configuration that provides the desired formulation characteristics is contemplated herein. Thus, in one aspect, the perforated microstructure can comprise a substantially spherical shape, eg, a hollow, suspended, spray-dried microsphere. However, collapsed, corrugated, deformed or crushed microparticles of any basic form or aspect ratio are also considered suitable.

  As applies to the suspended particles described herein, the porous microstructure can be formed from any biocompatible material that does not substantially degrade or dissolve in the selected suspension medium. Although a wide variety of materials can be used to form the particles, in some embodiments, the structural matrix is associated with or includes a surfactant, such as a phospholipid or fluorosurfactant. Although not required, the incorporation of a compatible surfactant into the porous microstructure, or more generally suspended particles, improves the stability of the respiratory dispersant and increases lung deposition. Suspension preparation can be facilitated.

  As used herein, the term “suspension medium” refers to a substance that provides a continuous phase in which active agent particles and suspended particles can be dispersed to provide a co-suspension liquid. The suspending medium used in the co-suspension liquid formulation described herein includes a propellant. As used herein, the term “propellant” is one that uses a sufficiently high vapor pressure at normal room temperature to inject a drug from an MDI can into a patient when the MDI metering valve is activated. It refers to the above pharmacologically inactive substances. 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 “respirable” generally refers to particles, aggregates, droplets, etc. that are sized to be inhaled to reach the lung airways.

  When used to refer to the co-suspension compositions described herein, the terms “physical stability” and “physically stable” refer to particle sizes due to aggregation, coagulation, and solution-mediated transition. Refers to a composition that is resistant to one or more of the changes and is capable of substantially maintaining the MMAD and fine particle dosage of suspended particles. In one aspect, physical stability can be assessed by exposing the composition to accelerated degradation conditions, such as by temperature cycling as described herein.

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

  When referring to an active agent, “highly potent” refers to an active agent that is therapeutically effective at a dose of about 10 μg / kg or less. Typical doses of highly potent active agents are generally in the range of up to about 100 μg.

  The terms “suspension stability” and “stable suspension” refer to a suspension formulation that can maintain the properties of a co-suspension of active agent particles and suspended particles over a period of time. In one aspect, suspension stability can be measured by the delivery dose uniformity achieved by the co-suspension compositions described herein.

  The term “substantially insoluble” means that the composition is either completely insoluble in a particular solvent or poorly soluble in that particular solvent. The term “substantially insoluble” means that the solubility of a particular solute is less than 1 part per 100 parts of solvent. The term “substantially insoluble” means “slightly” as shown in Table 16-1 on Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott, William & Wilkins, 2006, page 212. Soluble "(100-1000 parts of solvent per part of solute)," very slightly soluble "(1000-10,000 parts of solvent per part of solute) and" substantially insoluble "(10,000 parts of solvent per part of solute) The definition of “exceeding part”.

  The term “surfactant” as used herein refers to an interface between two immiscible phases (such as an interface between water and an organic polymer solution, a water / air interface, or an organic solvent / air interface). Any drug that preferentially adsorbs. Surfactants generally have a hydrophilic portion and a lipophilic portion, and when adsorbed on fine particles, the portion that does not attract the coated particles similarly tends to be directed to the continuous phase to reduce particle aggregation. In some embodiments, surfactants can promote drug adsorption and increase drug bioavailability.

  A “therapeutically effective amount” is the amount of a compound that achieves a therapeutic effect by inhibiting a disease or disorder in a patient or by prophylactically inhibiting or preventing the onset of a disease or disorder. A therapeutically effective amount reduces to some extent one or more symptoms of the patient's disease or disorder; partially or completely reduces one or more physiological or biochemical parameters associated with or causing the disease or disorder. It can be any amount that returns to normal; and / or reduces the likelihood of developing a disease or disorder.

  The terms `` chemically stable '' and `` chemical stability '' are the restrictions that individual degradation products of the active agent are identified by regulatory requirements during the shelf life of the product for human use (e.g. , Less than 1% of the total peak area of chromatography according to ICH guidance Q3B (R2)) and there is an acceptable mass balance between the active agent assay and the total degradation products (eg in ICH guidance Q1E Refers to a co-suspension formulation (as defined).

II. Compositions The compositions described herein comprise a co-suspension comprising two or more active agents and comprising a suspending medium, one or more active agent particles, and one or more suspended particles. is there. Of course, the compositions described herein can optionally include one or more additional ingredients. In addition, variations and combinations of the ingredients of the compositions described herein can be used.

  The co-suspension composition according to the present description can be embodied in a variety of different formulations. In certain embodiments, the composition described herein comprises a first activity provided in the form of active agent particles co-suspended with at least one suspended particle incorporating a second active agent. Contains agents. In other embodiments, the compositions described herein are co-suspended with at least one suspended particle that incorporates an active agent different from that contained within any of the active agent particles. Two or more active agents supplied in the form of two or more different types of active agent particles. In a still further aspect, the composition described herein comprises at least one active agent that incorporates an active agent that may be the same as or different from that contained in any of the active agent particles. Two or more active agents are provided in the form of two or more different types of active agent particles co-suspended with the suspended particles. In a still further aspect, the composition described herein is provided in the form of two or more different types of active agent particles co-suspended with one or more types of suspended particles that do not include an active agent. Containing one or more active agents. Where a composition described herein comprises two or more active agent particles, such a composition can be referred to as a “multi” co-suspension. For example, a composition comprising two active agent particles co-suspended with one or more suspended particles may be referred to as a dual co-suspension and may be referred to as one or more suspended particles. A composition comprising three active agent particles co-suspended with turbid particles can be referred to as a triple-co-suspension.

  In the compositions according to the present description, the active agent particles and the suspended particles are co-located in the suspending medium, even if many different types of active agent particles are present in the composition. As such, the active agent particles exhibit association with the suspended particles. In general, there is a density difference between different types of particles and the medium in which the particles are suspended (e.g., a propellant or propellant system), so buoyancy causes a lower density than the propellant. The particles cream and particles that are denser than the propellant settle. Therefore, in suspensions consisting of a mixture of different types of particles with different densities or different tendency to solidify, the settling or creaming behavior is considered to be specific to each of the different particle types and is suspended. It is thought that various particle species in the turbid medium are separated.

  However, the combination of propellant, active agent particles, and suspended particles described herein is a combination of two or more active agents where the active agent particles and suspended particles are co-located within the propellant. (I.e., after sufficient time for cream or sedimentation layer formation, the suspended and active particles are substantially separated from each other, such as by differential sedimentation or creaming). The active agent particles associate with the suspended particles so that they do not show general separation). In certain embodiments, for example, the compositions described herein can be obtained by centrifuging suspended particles with temperature fluctuations and / or accelerations up to, for example, 1 g, 10 g, 35 g, 50 g, and 100 g. A co-suspension is formed that remains associated with the activator particles when subjected to amplified buoyancy. However, the co-suspensions described herein need not be defined by a specific threshold force of association. For example, the co-suspensions contemplated herein have substantial separation of active agent particles and suspended particles within the continuous phase formed by the suspending medium under typical patient use conditions. This can be accomplished well when the active agent particles are associated with suspended particles.

  Co-suspensions of active agent particles and suspended particles according to the present description provide desirable chemical stability, suspension stability and active agent delivery characteristics. For example, in certain embodiments, when present in an MDI can, the co-suspensions described herein are: coagulation of active agent material; differential sedimentation or creaming of active agent particles and suspended particles; Solution-mediated transfer of active substance; chemical decomposition of the components of the formulation (including active substance or surfactant); and of the loss of active agent to the closure system, especially the surface of the metering valve component One or more can be inhibited. Such properties are substantially maintained until the desired fine particle fraction, fine particle dose and delivery dose uniformity characteristics are achieved and the MDI can containing the co-suspension formulation is substantially empty. It serves to achieve and maintain aerosol performance when the co-suspension formulation is delivered from MDI. Furthermore, the co-suspensions according to the present description do so, for example, while utilizing relatively simple HFA suspension media that do not require modification by the addition of co-solvents, antisolvents, solubilizers or adjuvants. Even when different active agents are delivered at significantly different doses, a physically and chemically stable formulation can be provided that provides certain administration characteristics to two or more active agents. Furthermore, the compositions produced as described herein eliminate or substantially eliminate the pharmaceutical effects often experienced with formulations containing multiple active agents when delivered from MDI. Avoid it. For example, as illustrated by the specific embodiments described in detail herein, the combination formulations described herein are formulated and delivered separately for each of the active agents contained therein. Provides delivery characteristics comparable to those of the same active agent.

  Providing a co-suspension according to the present description can also simplify the formulation, delivery and administration of the desired active agent. Without being bound by any particular theory, the delivery of the active agent contained within such dispersions, physical stability, by achieving a co-suspension of the active agent particles and the suspended particles And administration can be substantially controlled through controlling the size, composition, form and relative amount of the suspended particles, and the dependence on the size and form of the active agent is believed to be relatively low. Further, in a specific embodiment, the pharmaceutical compositions described herein can be formulated with a non-CFC propellant or propellant system that is substantially free of antisolvents, solubilizers, co-solvents or adjuvants.

  A co-suspension composition formulated according to the present teachings can inhibit physical and chemical degradation of the active agent contained therein. For example, in certain aspects, the compositions described herein can inhibit one or more of chemical degradation, coagulation, aggregation and solution-mediated transfer of the active agent contained in the composition. Due to the chemical and suspension stability provided by the co-suspension compositions described herein, at least one of the active agents to be delivered is very potent and the delivery dose of each active agent is Even in cases that vary considerably, the composition can be distributed in a manner that achieves the desired delivered dose uniformity (DDU) for a large number of active agents until the MDI can is empty.

  Co-suspension compositions described herein comprising two or more active agents can achieve ± 30% or better DDU for each of the active agents contained therein. In one such embodiment, the compositions described herein achieve a DDU of ± 25% or better for each of the active agents contained therein. In another such embodiment, the compositions described herein achieve a DDU of ± 20% or better for each of the active agents contained therein. Further, the co-suspension composition according to the present description functions to substantially maintain the performance of the FPF and FPD until the MDI can is empty, even after exposure to accelerated degradation conditions. For example, the composition according to the present description remains high enough to correspond to 80%, 90%, 95% or more of the original FPF or FPD performance even after exposure to accelerated degradation conditions To do.

  The co-suspension compositions described herein provide the added benefit of achieving such performance even when formulated with non-CFC propellants. In certain embodiments, the compositions described herein can be formulated with a suspension medium that includes only one or more non-CFC propellants, even though the target DDU, FPF, or FPD is It is not necessary to achieve one or more and modify the characteristics of the non-CFC propellant, such as by the addition of one or more co-solvents, antisolvents, solubilizers, adjuvants or other propellant modifiers.

(i) Suspension medium The suspension medium included in the compositions described herein comprises one or more propellants. In general, propellants suitable for use as suspending media are propellant gases that can be liquefied under pressure at room temperature and that are safe and toxicologically harmless upon inhalation or topical use. In addition, it is desirable that the propellant selected does not react significantly with the suspended and active agent particles. Exemplary compatible propellants include hydrofluoroalkanes (HFA), perfluorinated compounds (PFC) and chlorofluorocarbons (CFC).

Specific examples of propellants that can be used to form the co-suspension suspension medium disclosed herein include the following: 1,1,1,2-tetrafluoroethane (CF ₃ CF 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. Further suitable propellant, short-chain hydrocarbons: C _1-4 hydrogen-containing chlorofluorocarbons (e.g. _{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 fluorocarbons (eg HFA) such as CHF ₂ CHF ₂ , CF ₃ CH ₂ F, CHF ₂ CH ₃ , and CF ₃ CHFCF ₃ ; and perfluorocarbons (eg CF ₃ CF ₃ And CF ₃ CF ₂ CF ₃ ).

  Specific fluorocarbons or fluorinated compound types that can be used as suspending media include: fluoroheptane, fluorocycloheptane, fluoromethylcycloheptane, fluorohexane, fluorocyclohexane, fluoropentane, fluorocyclopentane, fluoromethylcyclo Examples include, but are not limited to, pentane, fluorodimethylcyclopentane, fluoromethylcyclobutane, fluorodimethylcyclobutane, fluorotrimethylcyclobutane, fluorobutane, fluorocyclobutane, fluoropropane, fluoroether, fluoropolyether and fluorotriethylamine. These compounds can be used alone or in combination with a more volatile propellant.

In addition to the aforementioned fluorocarbons and hydrofluoroalkanes, various exemplary chlorofluorocarbons and substituted fluorinated compounds can also be used as suspending media. In this _{case, FC-11 (CCl 3 F} ), FC-11B1 (CBrCl 2 F), FC-11B2 (CBr 2 ClF), FC12B2 (CF 2 Br 2), 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, but environmental We recognize that it may be accompanied by concerns. Accordingly, each of these compounds can 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 can be formed from a single propellant. In other embodiments, a combination of propellants can be used to form a suspending medium. In some embodiments, certain physical characteristics selected to mix relatively volatile compounds with lower vapor pressure ingredients to increase stability or increase bioavailability of the dispersed active agent. Can be provided. In some embodiments, lower vapor pressure compounds will include fluorinated compounds (eg, fluorocarbons) with boiling points greater than about 25 ° C. In some embodiments, lower vapor pressure fluorinated compounds for use in suspending media include: perfluorooctyl bromide C ₈ F ₁₇ Br (PFOB or perflubron), dichlorofluorooctane C ₈ F ₁₆ Mention may be made of Cl ₂ , perfluorooctylethane C ₈ F ₁₇ C ₂ H ₅ (PFOE), perfluorodecyl bromide C ₁₀ F ₂₁ Br (PFDB) or perfluorobutylethane C ₄ F ₉ C ₂ H ₅ . In certain embodiments, these lower vapor pressure compounds are present at relatively low levels. Such compounds can be added directly to the suspension medium or can be associated with the suspended particles.

  Suspension media included in the compositions described herein are formed from a propellant or propellant system that is substantially free of additional materials (e.g., anti-solvents, solubilizers, co-solvents or adjuvants, etc.). can do. For example, in some embodiments, the suspending medium can be formed from a non-CFC propellant or propellant system (such as an HFA propellant or propellant system) that is substantially free of additional materials. Such an embodiment simplifies the formulation and manufacture of a pharmaceutical composition suitable for respiratory delivery of the active agent contained 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 to be delivered, the suspending medium utilized will include substances in addition to the propellant or propellant system. be able to. Such additional materials include, for example, the following: suitable anti-solvents, solubilizers, co-solvents or adjuvants to adjust the vapor pressure or stability of the formulation, or the solubility of the suspended particles, for example. One or more of them can be mentioned. For example, propane, ethanol, isopropyl alcohol, butane, isobutane, pentane, isopentane or dialkyl ether (eg, dimethyl ether) can be incorporated with the propellant in the suspending medium. Similarly, the suspending medium can contain volatile fluorocarbons. In other embodiments, one or both of polyvinyl pyrrolidone (PVP) or polyethylene glycol (PEG) can be added to the suspension medium. One or more desired functional characteristics can be achieved by adding PVP or PEG to the suspension medium, and in one example, PVP or PEG can be added to the suspension medium as a crystal growth inhibitor. In general, when using volatile co-solvents or adjuvants, such adjuvants or co-solvents can be selected from known hydrocarbon or fluorocarbon materials and occupy up to about 1% by weight of the suspending medium. Can do. For example, when a co-solvent or adjuvant is incorporated into the suspending medium, the co-solvent or adjuvant can comprise less than about 0.01%, less than 0.1%, or less than 0.5% by weight of the suspending medium. When PVP or PEG is included in the suspending medium, such components may be included at up to about 1% by weight (w / w), or less than about 0.01% by weight of the suspending medium, 0.1% % Or less than 0.5% by weight.

(ii) Active agent particles The active agent particles contained in the co-suspensions described herein can be dispersed and suspended in a suspending medium and are suitable for respiration from the co-suspension. Formed from a material sized to facilitate delivery of the particles. Thus, in one aspect, the active agent particles are provided as a micronized material wherein at least 90% by volume of the active agent particles exhibit an optical diameter of about 7 μm or less. In other embodiments, the active agent particles are micronized wherein at least 90% by volume of the active agent 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. Provided as a substance. In other embodiments, the active agent particles are provided as a micronized material wherein at least 90% by volume of the active agent particles exhibit an optical diameter selected from 6 μm or less, 5 μm or less, 4 μm or less, or 3 μm or less. In another aspect, the active agent particles are provided as a micronized material wherein at least 50% by volume of the active agent particle material exhibits an optical diameter of about 4 μm or less. In further embodiments, the active agent particles are provided as a micronized material wherein at least 50% by volume of the active agent particle material exhibits 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. The In still further embodiments, the active agent particles are selected from the range of 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 at least 50% by volume of the active agent particles. Supplied as a finely divided substance showing an optical diameter.

  The active agent particles may be formed entirely from the active agent or may be formulated to include one or more active agents in combination with one or more excipients or adjuvants. In certain embodiments, the active agent present in the active agent particles can be completely or substantially crystalline, i.e., the majority of the active agent molecules are regularly extended over the exterior surface for extended periods of time. Arranged in a repeating pattern. In another aspect, the active agent particles can include an active agent that exists in both a crystalline state and an amorphous state. In yet another aspect, the active agent particles can include an active agent that exists in a substantially amorphous state, i.e., the active agent molecule is entirely amorphous in nature and is maintained for an extended period of time. There is no regular repeating array. In yet a further aspect, when two or more active agents are present as active agent particles, all such active agents can be present in crystalline or substantially crystalline form. In an alternative embodiment using two or more active agents present, at least one such active agent can be present in crystalline or substantially crystalline form and at least one other active agent is non- It can exist in a crystalline state.

  When 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 are chemically and chemically active agents used. Can be selected based on physical characteristics. In addition, excipients suitable for the formulation of active agent particles include those described herein associated with suspended particles. In certain embodiments, for example, the active agent particles are, for example, lipids, phospholipids, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, synthetic or natural polymers or surfactants associated with suspended particles. It can be formulated with one or more of the listed substances.

  In other embodiments, for example, the active agent is added to a solution of one or more of lipids, phospholipids, carbohydrates, amino acids, metal salts, organic salts, peptides, proteins, alditols, synthetic or natural polymers or surfactants, It can be spray-dried into suspended particles containing the active agent in the substance forming the suspended particles.

  Any suitable process can be used to obtain a micronized active agent material for use as or included in the active agent particles or suspended particles described herein. Such processes include: micronization by a milling or grinding process, crystallization or recrystallization process, and processes using precipitation from a supercritical or near supercritical solvent, spray drying, spray freeze drying or freeze drying. However, it is not limited to these. Patent references that teach suitable methods for obtaining micronized activator particles include, for example, U.S. Patent No. 6,063,138, U.S. Patent No. 5,858,410, U.S. Patent No. 5,851,453, U.S. Patent No. 5,833,891, U.S. Patent No. 5,707,634. And International Patent Application Publication No. WO2007 / 009164. Where the active agent particles comprise an active agent material formulated with one or more excipients or adjuvants, micronized active agent particles can be formed using one or more of the processes described above, and so on. Using this process, active agent particles having a desired size distribution and particle configuration can be obtained.

  The activator particles can be provided in any suitable concentration within the suspending 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 are present at a concentration selected from about 0.05 mg / ml to about 20 mg / ml, from about 0.05 mg / ml to about 10 mg / ml, and from about 0.05 mg / ml to about 5 mg / ml. can do.

  A variety of therapeutic or prophylactic agents can be utilized as active agents in the co-suspension compositions disclosed herein. Exemplary active agents include those that can be administered in the form of an aerosolized drug, and suitable active agents for use in the compositions described herein are dispersed within a selected suspension medium. Present (e.g., are substantially insoluble or exhibit solubility in a suspending medium that substantially maintains a co-suspension formulation) or may be formulated in such a manner And can form a co-suspension with the suspended particles and is easily taken up so that it can breathe in a physiologically effective amount. The active agents that can be utilized in forming the active agent particles described herein can have a variety of biological activities.

Examples of specific active agents that can be included in the compositions according to the present description include, for example: short-acting beta agonists such as vitorterol, carbuterol, fenoterol, hexoprenalin, isoprenaline (isoproterenol) , Levosalbutamol, orciprenaline (metaproterenol), pyrbuterol, procaterol, limiterol, salbutamol (albuterol), terbutaline, tubuterol, reproterol, ipratropium and epinephrine; long acting beta ₂ adrenergic receptor agonists (LABA) such as bambuterol , Clenbuterol, formoterol, salmeterol; very long acting β ₂ adrenergic receptor agonists such as carmoterol, milveterol, indacaterol, And adamantyl-inducible β ₂ agonists containing saligenin or indole; corticosteroids such as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone, prednisone and triamcinolone; anti-inflammatory drugs such as fluticasone propionate, two Beclomethasone propionate, flunisolide, budesonide, tripedane, cortisone, prednisone, prednisolone, dexamethasone, betamethasone or triamcinolone acetonide; antitussives such as noscapine; bronchodilators such as ephedrine, adrenaline, fenoterol, pronoterol, , Salbutamol, albuterol, salmeterol, terbutaline As well as muscarinic antagonists (such as long-acting muscarinic antagonists (LAMA)), such as glycopyrrolate, dexipirronium, scopolamine, tropicamide, pirenzepine, dimenhydrinate, tiotropium, darotropium, acridinium, tropium, It can be ipratropium, atropine, benztropine or oxitropium.

  Where appropriate, the active agents provided in the composition, such as but not limited to those specifically described herein, are salts (eg, alkali metal or amine salts, or acid addition salts). As) or as esters, solvates (hydrates), derivatives or free bases. Furthermore, the active agent can be present in any crystalline form or isomeric form or in the form of a mixture of isomeric forms, for example as a pure enantiomer, a mixture of enantiomers, as a racemate or as a mixture thereof. In this case, the active agent form can 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.

  In certain embodiments, the active agents included in the compositions described herein are one or more potent, as the disclosed compositions provide reproducible delivery of very low doses of active agents. Or it can be selected from highly potent active agents. For example, in certain embodiments, the compositions described herein are selected from about 100 μg to about 100 mg per dose, about 100 μg to about 10 mg per dose, and about 100 μg to 1 mg per dose One or more potent active agents to be delivered in a given dose can be included. In other embodiments, the compositions described herein have a maximum of about 80 μg per dose, a maximum of about 40 μg per dose, a maximum of about 20 μg per dose, a maximum of about 10 μg per dose. Or a combination of two or more potent or highly potent active agents to be delivered at a dose selected from about 10 μg to about 100 μg per dose. In more specific embodiments, the compositions described herein have from about 0.1 to about 2 μg per dose, from about 0.1 to about 1 μg per dose, and from about 0.1 to about 0.5 μg per dose. A combination of two or more highly potent active agents to be delivered at a dose selected from:

In certain embodiments, the compositions described herein include a LABA active agent. In such embodiments, the composition comprises a LABA active agent in combination with a LAMA active agent or a corticosteroid active agent. In another such embodiment, the composition comprises a LAMA active agent in combination with a LABA active agent and a corticosteroid. In such embodiments, the LABA activators include, for example, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin or indole and adamantyl-inducible β ₂ agonists, and any pharmaceuticals thereof It can be selected from chemically acceptable salts, esters, isomers or solvates. In certain such embodiments, the active agent is selected from formoterol and pharmaceutically acceptable salts, esters, isomers or solvates thereof.

  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, commonly used as a racemic fumaric acid dihydrate salt in pharmaceutical compositions. Where appropriate, formoterol can be used in the form of a salt (eg, as an alkali metal or amine salt, or acid addition salt), as an ester, or as a solvate (hydrate). Furthermore, formoterol can be in any crystalline form or isomeric form or a mixture of isomeric forms, such as pure enantiomers, mixtures of enantiomers, racemates or mixtures thereof. In this case, the formoterol form can be selected to optimize the activity and / or stability of formoterol and / or to minimize the solubility of formoterol in the suspension medium. Examples of pharmaceutically acceptable salts of formoterol include the following: inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), and organic acids (fumaric acid, maleic acid, acetic acid, lactic acid, citric acid) , Tartaric acid, ascorbic acid, succinic acid, glutaric acid, gluconic acid, tricarballylic acid, oleic acid, benzoic acid, p-methoxybenzoic acid, salicylic acid, o- and p-hydroxybenzoic acid, p-chlorobenzoic acid, methanesulfone Acid, p-toluenesulfonic acid and 3-hydroxy-2-naphthalenecarboxylic acid). Formoterol hydrates are described, for example, in US Pat. No. 3,994,974 and US Pat. No. 5,684,199. Specific crystal forms are described, for example, in International Patent Publication No. WO95 / 05805, and specific isomers of formoterol are described in US Pat. No. 6,040,344.

  In certain embodiments, the formoterol material utilized to form the formoterol particles is formoterol fumarate, and in one such embodiment, formoterol fumarate is present in the dihydrate form. Where the compositions described herein comprise formoterol, in certain embodiments, the compositions described herein comprise formoterol in an amount of about 0.5 μg to about 30 μg, 0.5 μg to about 1 μg, It can be included at a concentration that achieves a delivery dose selected from 1 μg to about 10 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. In other embodiments, the compositions described herein are selected from up to about 30 μg, up to about 10 μg, up to about 5 μg, up to about 2.5 μg, up to about 2 μg, or up to about 1.5 μg of formoterol per actuation of MDI. In an amount sufficient to provide a desired delivery dose. When a composition described herein includes formoterol as an active agent to achieve a delivery dose as described herein, in certain embodiments, the amount of formoterol included in the composition is, for example, about It can be selected from 0.01 mg / ml to about 1 mg / ml, from about 0.01 mg / ml to about 0.5 mg / ml, and from about 0.03 mg / ml to about 0.4 mg / ml.

  When the pharmaceutical co-suspension composition described herein comprises a LABA active agent, in certain embodiments, the active agent is salmeterol (any pharmaceutically acceptable salt, ester, isomer or solvate thereof). Inclusive). Salmeterol can be used to treat inflammatory or obstructive pulmonary diseases and disorders (such as those described herein). If salmeterol is also included as the LABA active agent, in some such embodiments, the composition can also include a LAMA active agent or a corticosteroid active agent. In other such embodiments, the composition comprises salmeterol in combination with a LAMA active agent and a corticosteroid. Salmeterol, pharmaceutically acceptable salts of salmeterol, and methods for their preparation 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 the LABA activator, in certain embodiments, the compositions described herein comprise salmeterol in an amount of about 2 μg to about 120 μg, about 4 μg to about 40 μg, about 8 μg to 20 μg per agonist of MDI, It can be included at a concentration that achieves a delivery dose selected from about 8 μg to about 40 μg, about 20 μg to about 40 μg, and about 12 μg to about 120 μg. In other embodiments, the compositions described herein select salmeterol from a maximum of about 120 μg, a maximum of about 40 μg, a maximum of about 20 μg, a maximum of about 10 μg, a maximum of about 8 μg or a maximum of about 6 μg per actuation of MDI. It can be included in an amount sufficient to provide a delivery dose. In order to achieve the target delivery dose described herein, when the composition described herein includes salmeterol as an active agent, in certain embodiments, the amount of salmeterol included in the composition is: For example, it can be selected from about 0.04 mg / ml to about 4 mg / ml, from about 0.04 mg / ml to about 2.0 mg / ml, and from about 0.12 mg / ml to about 0.8 mg / ml. For example, the compositions described herein provide sufficient salmeterol to provide a target delivery dose 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 actuation of MDI. Can be included. In yet other embodiments, the compositions described herein comprise sufficient salmeterol to provide a target delivery dose selected from a maximum of about 100 μg, a maximum of about 40 μg, or a maximum of about 15 μg per actuation of MDI. Can do.

  In certain embodiments, the compositions described herein comprise a long acting muscarinic antagonist (LAMA) active agent. Examples of LAMA activators that may be used in the compositions described herein include the following: glycopyrrolate, doxypyronium, tiotropium, trospium, acridinium and darotropium (any pharmaceutically acceptable salt thereof) , Esters, isomers or solvates). In some embodiments, the compositions described herein comprise a LAMA active agent in combination with a LABA active agent or a corticosteroid. In other such embodiments, the compositions described herein comprise a LAMA active agent in combination with both a LABA active agent and a corticosteroid active agent. When the composition includes a LAMA active agent, in certain embodiments, glycopyrrolate (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) can be selected.

  Glycopyrrolate can be used to treat inflammatory or obstructive pulmonary diseases and disorders (such as those described herein). As an anticholinergic agent, glycopyrrolate provides a beneficial antisecretory effect for use in the treatment of lung diseases and disorders characterized by increased mucus secretion. Glycopyrrolate is a quaternary ammonium salt. Depending on the case, glycopyrrolate should be used in the form of a salt (for example as an alkali metal or amine salt, or acid addition salt), ester, solvate (hydrate) or selected isomer. Can do. Furthermore, glycopyrrolate can be in any crystalline form or isomeric form or a mixture of isomeric forms, such as pure enantiomers, mixtures of enantiomers, racemates or mixtures thereof. In this case, the form of glycopyrrolate is selected to optimize the activity and / or stability of glycopyrrolate and / or to minimize the solubility of glycopyrrolate in the suspension medium. be able to. Suitable counter ions are, for example: fluoride ion, chloride ion, bromide ion, iodide ion, nitrate ion, sulfate ion, phosphate ion, formate ion, acetate ion, trifluoroacetate ion, propionate ion , Butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl acetate or triphenyl acetate, o-hydroxybenzoate With pharmaceutically acceptable counter ions such as acid ion, p-hydroxybenzoate ion, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate ion and benzenesulfonate ion is there. Certain embodiments of the compositions described herein use the bromide salt of glycopyrrolate, ie 3-[(cyclopentyl-hydroxyphenylacetyl) oxy] -1,1-dimethylpyrrolidinium bromide, It can be prepared by the procedure described in US Pat. No. 2,956,062.

  When the composition described herein comprises glycopyrrolate, in certain embodiments, the composition has from about 10 μg to about 100 μg, from about 15 μg to about 100 μg, from about 15 μg to about 80 μg, per actuation of MDI, and Sufficient glycopyrrolate can be included to provide a delivery dose selected from about 10 μg to about 80 μg. In other such embodiments, the formulation is sufficient to provide a delivery dose selected from a maximum of about 100 μg, a maximum of about 80 μg, a maximum of about 40 μg, a maximum of about 20 μg or a maximum of about 10 μg per actuation of MDI. Includes pyrolates. In yet a further aspect, the formulation comprises sufficient glycopyrrolate to provide a delivery dose selected from about 9 μg, 18 μg, 36 μg and 72 μg per actuation of MDI. To achieve the delivery doses described herein, when the composition described herein includes glycopyrrolate as an active agent, in certain embodiments, the glycopyrrolate contained in the composition The amount can be selected, for example, from about 0.04 mg / ml to about 2.25 mg / ml.

  In other embodiments, tiotropium (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) is selected as the LAMA active agent for inclusion in the compositions described herein. can do. Tiotropium is a known long acting anticholinergic suitable for use in the treatment of diseases or disorders involving inflammation or obstruction of the lung (such as those described herein). Tiotropium (including tiotropium in crystalline and pharmaceutically acceptable salt form) is described, for example, in U.S. Patent No. 5,610,163, U.S. Patent No. RE398220, U.S. Patent No. 6,777,423 and U.S. Patent No. 6,908,928. . When the composition described herein comprises tiotropium, in certain embodiments, the composition has from about 2.5 μg to about 25 μg, from about 4 μg to about 25 μg, from about 2.5 μg to about 20 μg, and from about 2.5 μg to about 20 μg, and Sufficient tiotropium can be included to provide a delivery dose selected from about 10 μg to about 20 μg. In other such embodiments, the formulation is sufficient to provide a delivery dose selected from up to about 25 μg, up to about 20 μg, up to about 10 μg, up to about 5 μg, or up to about 2.5 μg per actuation of MDI. Contains tiotropium. In yet a further aspect, the formulation comprises sufficient tiotropium to provide a delivery dose selected from about 3 μg, 6 μg, 9 μg and 18 μg per actuation of MDI. In order to achieve the delivery doses described herein, when a composition described herein includes tiotropium as an 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 yet other embodiments, the compositions described herein comprise corticosteroids. Such active agents include, for example, beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, mometasone, prednisone and triamcinolone (including any pharmaceutically acceptable salts, esters, isomers or solvates thereof). You can choose from. In some embodiments, such compositions comprise a corticosteroid active agent in combination with a LAMA active agent or a LABA active agent. In other such embodiments, the composition comprises a corticosteroid active agent in combination with a LAMA active agent and a LABA active agent. When the composition includes a corticosteroid active agent, mometasone can be selected in certain embodiments.

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

  Where the composition described herein comprises mometasone, in certain embodiments, the composition comprises mometasone (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) Provides a target delivery dose selected from about 20 μg to about 400 μg, about 20 μg to about 200 μg, about 50 μg to about 200 μg, about 100 μg to about 200 μg, about 20 μg to about 100 μg, and about 50 μg to about 100 μg per actuation of MDI Contains enough to do. In yet other embodiments, the compositions described herein comprise mometasone (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) up to about 400 μg per agonist of MDI. , Up to about 200 μg or up to about 100 μg can be included in an amount sufficient to provide a target delivery dose.

  In other embodiments, the compositions described herein comprise a corticosteroid selected from fluticasone and budesonide. Both fluticasone and budesonide are suitable for use in the treatment of conditions involving inflammation or obstruction of the lung (such as those described herein). Fluticasone, pharmaceutically acceptable salts of fluticasone (such as fluticasone propionate), and the preparation of such materials are known, for example, U.S. Pat.No. 4,335,121, U.S. Pat. In the issue. Budesonide is also known and is described, for example, in US Pat. No. 3,929,768. In certain embodiments, the compositions described herein comprise fluticasone (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) from about 20 μg to about 20 μg per agonist of MDI. It can be included in an amount sufficient to provide a target delivery dose selected from 200 μg, about 50 μg to about 175 μg, and about 80 μg to about 160 μg. In other embodiments, the compositions described herein comprise fluticasone (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) up to about 175 μg per agonist of MDI, It can be included in an amount sufficient to provide a target delivery dose selected from up to about 160 μg, up to about 100 μg, or up to about 80 μg. In certain embodiments, the compositions described herein contain budesonide (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) from about 30 μg to about 30 μg per agonist of MDI. It can be included in an amount sufficient to provide a target delivery dose selected from 240 μg, about 30 μg to about 120 μg, and about 30 μg to about 50 μg. In yet other embodiments, the compositions described herein comprise budesonide (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) up to about 240 μg per agonist of MDI. A sufficient amount to provide a target delivery dose selected from a maximum of about 120 μg or a maximum of about 50 μg.

  In each embodiment, the compositions described herein include two or more active agents. In some embodiments, the composition comprises a combination of two or more active agent particles that may be co-suspended with a single type of suspended particle. Alternatively, the composition can include two or more active agent particles co-suspended with two or more different species of suspended particles. As yet another alternative, the compositions described herein can include a single type of active agent particle suspended with a single type of suspended particle, wherein the single type of active agent particle. Incorporates one or more active agents, and a single type of suspended particle incorporates one or more active agents. Furthermore, the compositions described herein may include two or more active agents combined within a single type of active agent particle. For example, if the active agent particles are formulated using one or more excipients or adjuvants in addition to the active agent material, such active agent particles may be separated into individual particles containing two or more different active agents. Can be included.

(iii) Suspended particles Suspended particles included in the co-suspension compositions described herein function to facilitate stabilization and delivery of the active agent included in the composition. Although various forms of suspended particles can be used, the suspended particles are typically pharmacologically inert that are inhalable and substantially insoluble in the selected propellant. Formed from material. In general, the majority of suspended particles are in a size suitable for respiration. Thus, in certain embodiments, the MMAD of the suspended particles will not exceed about 10 μm but not less than about 500 nm. In another embodiment, the MMAD of the suspended particles is from about 5 μm to about 750 nm. In another embodiment, the MMAD of the suspended particles is about 1 μm to about 3 μm. When used in one embodiment for nasal delivery from MDI, the MMAD of the suspended particles is between 10 μm and 50 μm.

  To achieve respirable suspended particles within the stated MMAD range, the suspended particles will typically exhibit a volume median optical diameter of about 0.2 μm to about 50 μm. right. In one aspect, the suspended particles exhibit a median optical diameter volume that does not exceed about 25 μm. In another embodiment, the suspended particles exhibit a median optical diameter volume 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 contained in the composition according to the present description can be adjusted, for example, depending on the amount of active agent particles and suspending medium used. In one aspect, the suspended particles are suspended at a concentration selected from about 1 mg / ml to about 15 mg / ml, about 3 mg / ml to about 10 mg / ml, 5 mg / ml to about 8 mg / ml, and about 6 mg / ml. Contained in turbid media. In another embodiment, the suspended particles are included in the suspending medium at a concentration of up to about 30 mg / ml. In yet another embodiment, the suspended particles are included in the suspending medium at a concentration of up to about 25 mg / ml.

  The relative amount of suspended particles versus active agent particles is selected to achieve a co-suspension as contemplated herein. A co-suspension composition may be achieved in which the amount of suspended particles, as 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 activator particles can be about 3: 1 to about 15: 1, alternatively about 2: 1 to 8: 1. Alternatively, the ratio of the total mass of suspended particles to the total mass of active particles can be greater than about 1, for example, up to about 1.5, up to about 1.5, depending on the nature of the suspended and active particles used. 5, up to about 10, up to about 15, up to about 17, up to about 20, up to about 30, up to about 40, up to about 50, up to about 60, up to about 75, up to about 100, up to about 150 and up to about 200 is there. In further embodiments, the ratio of the total mass of suspended particles to the total mass of active agent 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 and about 170.

  In other embodiments, the amount of suspended particles as measured by mass is less than the amount of active agent particles. For example, in certain embodiments, the mass of suspended particles can be only 20% of the total mass of active agent particles. However, in some embodiments, the total mass of suspended particles may be close to or equal to the total mass of active agent particles.

  One or more pharmaceutically acceptable suspension particles suitable for use in the compositions described herein are suitable for inhalation delivery and do not substantially degrade or dissolve in the suspension medium. It can be formed from substances or excipients. In one aspect, the porous microstructure defined herein can be used as suspended particles. Exemplary excipients that can be used in the formulation of suspended particles described herein include: (a) carbohydrates such as monosaccharides (fructose, galactose, glucose, D-mannose, sorbose, etc.); Sugars (such as sucrose, lactose, trehalose, cellobiose); cyclodextrins (such as 2-hydroxypropyl-β-cyclodextrin); and polysaccharides (such as raffinose, maltodextrin, dextran, starch, chitin, chitosan, inulin); b) amino acids (alanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine, leucine, isoleucine, valine, etc.); etc .; (c) metal salts and organic salts prepared from organic acids and organic bases (sodium citrate, Sodium ascorbate, magnesium gluconate, sodium gluconate, (D) peptides and proteins (aspartame, trileucine, human serum albumin, collagen, gelatin, etc.); (e) alditols (mannitol, xylitol, etc.); (f) synthetic or natural Or a combination thereof (polylactide, polylactide-glycolide, cyclodextrin, polyacrylate, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydride, polylactam, polyvinylpyrrolidone, hyaluronic acid, polyethylene glycol, etc.); and (g) fluorinated compound And surfactants including non-fluorinated compounds such as saturated and unsaturated lipids, nonionic surfactants, nonionic block copolymers, ionic surfactants and combinations thereof. But it is not limited to. In certain embodiments, the suspended particles can include a calcium salt (such as calcium chloride) as described, for example, in US Pat. No. 7,442,388.

In addition, phospholipids derived from both natural and synthetic sources can be used in the preparation of suspended particles suitable for use in the compositions described herein. In certain embodiments, the selected phospholipid will have a gel to liquid crystal phase transition greater than about 40 ° C. Exemplary phospholipids are relatively long chain (i.e., C ₁₆ -C ₂₂₎ saturated lipids, that the acyl chain length containing saturated phospholipids, such as saturated phosphatidylcholine 16C or 18C (palmitoyl and stearoyl) it can. Exemplary phospholipids include: dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, diarachidyl phosphatidylcholine, dibehenoyl phosphatidylcholine, diphosphatidylglycerol, short chain phosphatidylcholine, long chain saturated phosphatidylethanolamine, long chain saturated phosphatidylserine Phosphoglycerides such as long chain saturated phosphatidylglycerol and long chain saturated phosphatidylinositol. Additional excipients are disclosed in PCT International Patent Application Publication No. WO 96/32149 and US Pat. Nos. 6,358,530, 6,372,258, and 6,518,239.

  In certain aspects, suspended particles can be formed using one or more lipids, phospholipids or sugars described herein. In some embodiments, the suspended particles include one or more surfactants. The use of suspended particles formed from or incorporating one or more surfactants can facilitate absorption of the selected active agent, thereby increasing bioavailability. Suspended particles described herein (eg, suspended particles formed using one or more lipids) can be formed to exhibit a desired surface rugosity (roughness). This can further improve aerosolization by further reducing particle-particle interactions and reducing the surface area available for particle-particle interactions. In further embodiments, where appropriate, lipids naturally present in the lung may be used in the formation of suspended particles. This is because such suspended particles may reduce opsonization (and thereby reduce phagocytosis by alveolar macrophages) and thus provide longer-lived controlled release particles to the lungs. .

  In another aspect, the suspended particles utilized in the compositions described herein are storage stable for selected active agents, similar to those disclosed in International Patent Application WO 2005/000267. You can choose to enhance sex. For example, in one embodiment, the suspended particles can include a pharmaceutically acceptable glass stabilizing excipient having a Tg of at least 55 ° C, at least 75 ° C, or at least 100 ° C. Suitable glass formers for use in the compositions described herein include: trileucine, sodium citrate, sodium phosphate, ascorbic acid, inulin, cyclodextrin, polyvinylpyrrolidone, mannitol, sucrose, One or more of trehalose, lactose and proline can be mentioned, but not limited thereto. Examples of additional glass forming excipients are disclosed in US Pat. Nos. RE37,872, 5,928,469, 6,258,341, and 6,309,671.

  The suspended 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 a perforated microstructure as described herein. When a perforated microstructure is used as suspended particles in the compositions described herein, the structure should be formed using one or more excipients as described herein. Can do. For example, in certain embodiments, the porous microstructure comprises: lipids, phospholipids, nonionic surfactants, nonionic block copolymers, ionic surfactants, biocompatible fluorosurfactants and It may comprise at least one of those combinations, especially those approved for use in the lung. Specific surfactants that can be used in the preparation of the porous microstructure include poloxamer 188, poloxamer 407, and poloxamer 338. Other specific surfactants include oleic acid or an alkali salt thereof. In one aspect, the porous microstructure comprises greater than about 10% w / w surfactant.

  In some embodiments, suspended particles can be prepared by forming an oil-in-water emulsion using a fluorocarbon oil (e.g., perfluorooctyl bromide, perfluorodecalin bromide), where the fluorocarbon oil is a long chain saturated phosphorous. It can be emulsified using a surfactant such as lipid. The resulting perfluorocarbon emulsion in water can then be treated with a high pressure homogenizer to reduce the size of the oil droplets. If it is desired to include the active agent within the matrix of the porous microstructure, the perfluorocarbon emulsion can be fed to the spray dryer, optionally using an active agent solution. As is well known, spray drying is a one-step process that converts a liquid feedstock into a dry particulate form. Spray drying has been used to obtain powdered pharmaceutical substances for various routes of administration (such as inhalation). Adjust the spray dryer operating conditions (inlet and outlet temperature, feed rate, atomization pressure, drying air flow rate and nozzle configuration, etc.) to provide the desired granules to provide the yield of the resulting dried microstructure The diameter can be obtained. Such a method of making exemplary perforated microstructures is disclosed in US Pat. No. 6,309,623 to Weers et al.

  The perforated microstructures described herein can also be formed by lyophilization and subsequent grinding or micronization. Freeze drying is a freeze drying process in which the composition is frozen and then water is sublimated from the composition. This process can be dried without using high temperatures. In yet a further aspect, the suspended particles can be made using a spray lyophilization process as disclosed in US Pat. No. 5,727,333.

  Further, the suspended particles described herein can include a bulking agent (such as polymeric particles). The polymeric polymer can be formed from a biocompatible and / or biodegradable polymer, copolymer or blend. In one aspect, polymers capable of forming aerodynamically light particles (such as functionalized polyester graft copolymers and biodegradable polyanhydrides) can be used. For example, polyester-based bulk eroding polymers (such as poly (hydroxy acids)) can be used. Polyglycolic acid (PGA), polylactic acid (PLA) or copolymers thereof can be used to form suspended particles. The polyester can contain charged groups or functionalizable groups (such as amino acids). For example, suspended particles can be formed from poly (D, L-lactic acid) and / or poly (D, L-lactic acid-co-glycolic acid) (PLGA) incorporating a surfactant such as DPPC. .

  Other possible polymer candidates for use in suspended particles include: polyamides, polycarbonates, polyalkylenes (polyethylene, polypropylene, poly (ethylene glycol), poly (ethylene oxide), poly (ethylene terephthalate) )), Polyvinyl compounds (such as polyvinyl alcohol, polyvinyl ethers and polyvinyl esters), polymers of acrylic acid and methacrylic acid, cellulose and other polysaccharides, and peptides or proteins, or copolymers or blends thereof. The polymers can be selected or modified to have appropriate in vivo stability and degradation rates for different controlled drug delivery applications.

  The compositions described herein can include two or more types of suspended particles. Furthermore, the composition according to the present description can comprise suspended particles comprising one or more active agents incorporated in the suspended particles. When the active agent is incorporated into the suspended particles, the suspended particles are considered to be of a size suitable for respiration and can be formulated and made using, for example, the methods and materials described herein.

  Compositions formulated according to the present teachings can inhibit the degradation of the active agent contained therein. For example, in certain embodiments, the compositions described herein inhibit one or more of coagulation, aggregation and solution-mediated transfer of the active agent substance contained in the composition. The pharmaceutical compositions described herein provide desirable delivery dose uniformity for each active agent contained in a combination of two or more active agents, even when using a combination that includes a strong and highly potent active agent. Suitable for MDI respiratory delivery in a manner that achieves (DDU). As illustrated in detail in the examples included herein, the compositions described herein empty the MDI can even when delivering very low doses of two or more active agents. Up to ± 30% or better DDU can be achieved for each active agent. In one such aspect, the compositions described herein achieve a DDU of ± 25% or better for each active agent until the MDI can is empty. In yet another such embodiment, the compositions described herein achieve an active agent DDU of ± 20% or better for each active agent until the MDI can is empty.

  The pharmaceutical compositions described herein also function to substantially maintain FPF and FPD performance until the MDI can is empty, even after exposure to accelerated degradation conditions. For example, the composition according to the present description maintains 80%, 90%, 95% or more of the performance of the original FPF and FPD until the MDI can is empty, even after exposure to accelerated degradation conditions. . The compositions described herein are formulated with non-CFC propellants while eliminating or substantially avoiding the pharmacological effects often experienced with compositions that incorporate multiple active agents. Providing the added benefit of achieving such performance. In certain embodiments, the compositions described herein use a suspending medium that includes only one or more non-CFC propellants, one or more co-solvents, anti-solvents, solubilizers, adjuvants or Achieve one or all of the desired DDU, FPF or FPD performance while formulating without the need to modify the characteristics of the non-CFC propellant, such as by adding other propellant modifying materials.

  In one aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Glycopyrrolate suspended in the suspension medium at a concentration sufficient to provide a glycopyrrolate delivery dose of about 15 μg to about 80 μg per actuation (any pharmaceutically acceptable salt, ester, A first active agent particle comprising an isomer or a solvate; and the suspension at a concentration sufficient to provide a formoterol delivery dose of from about 2 μg to about 10 μg per actuation of a metered dose inhaler A second active agent particle comprising formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) suspended in a medium; and an optical of about 1.5 μm to about 10 μm Suitable for multiple breaths, including perforated microstructures with a median diameter volume And a turbid particles, the first and second type of active agent particles form a co-suspension in association with a plurality of suspended particles. In one such embodiment, the ratio of the total mass of suspended particles to the total mass of the first and second active agent particles is about 3: 1 to about 15: 1, and about 2: 1 to 8: 1. Selected from.

  In another aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; and a metered dose inhaler Of tiotropium (any pharmaceutically acceptable salt, ester, isomer thereof, or suspension thereof) suspended in the suspension medium at a concentration sufficient to provide about 5 μg to about 20 μg of tiotropium delivery dose per A first active agent particle comprising a solvate; and a concentration of about 2 μg to about 10 μg of formoterol delivered per actuation of a metered dose inhaler in the suspension medium at a concentration sufficient to provide A second active agent particle comprising suspended formoterol (including any pharmaceutically acceptable salt, ester, isomer, or solvate thereof); and a median optical diameter volume of about 1.5 μm to about 10 μm Suspension suitable for multiple breaths including perforated microstructure The active agent particles of the first and second types associate with a plurality of suspended particles to form a co-suspension. In one such embodiment, the ratio of the total mass of suspended particles to the total mass of the first and second active agent particles is about 3: 1 to about 15: 1, and about 2: 1 to 8: 1. Selected from.

  In another aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; and a metered dose inhaler Glycopyrrolate (any pharmaceutically acceptable salt, ester thereof) suspended in the suspension medium at a concentration sufficient to provide a glycopyrrolate delivery dose of about 15 μg to about 80 μg per actuation of Suitable for multiple breathing, including formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof); Wherein the plurality of suspended particles exhibit a median optical diameter volume of about 1.5 μm to about 10 μm and a formoterol delivery dose of about 2 μg to about 10 μg per actuation of a metered dose inhaler Contained in the suspension medium at a concentration sufficient to provide In association with a plurality of active agent particles to form a co-suspension. In one such embodiment, the ratio of the total mass of suspended particles to the total mass of the first and second active agent particles is about 3: 1 to about 15: 1, and about 2: 1 to 8: 1. Selected from.

  In another aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; and a metered dose inhaler Of tiotropium (any pharmaceutically acceptable salt, ester, isomer thereof, or suspension thereof) suspended in the suspension medium at a concentration sufficient to provide about 5 μg to about 20 μg of tiotropium delivery dose per A plurality of active agent particles comprising a solvate; and a plurality of respirable suspension particles comprising formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) Wherein the plurality of suspended particles exhibit a median optical diameter volume of about 1.5 μm to about 10 μm and provide a formoterol delivery dose of about 2 μg to about 10 μg per actuation of a metered dose inhaler. Contained in the suspension medium at a concentration sufficient for It associates with a plurality of activator particles to form a co-suspension. In one such embodiment, the ratio of the total mass of suspended particles to the total mass of the first and second active agent particles is about 3: 1 to about 15: 1, and about 2: 1 to 8: 1. Selected from.

  In another aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; and a metered dose inhaler Glycopyrrolate (any pharmaceutically acceptable salt, ester thereof) suspended in the suspension medium at a concentration sufficient to provide a glycopyrrolate delivery dose of about 15 μg to about 80 μg per actuation of A first active agent particle comprising an A second active agent particle comprising formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) suspended in a turbid medium; and beclomethasone, budesonide, ciclesonide, flunisolide , Fluticasone, methyl A third active agent particle comprising a corticosteroid selected from prednisolone, mometasone, prednisone and triamcinolone, including any pharmaceutically acceptable salt, ester, isomer or solvate thereof; and about 1.5; a plurality of respirable suspension particles comprising a porous microstructure exhibiting a median optical diameter volume of from about 10 μm to about 10 μm, wherein the first, second and third types of activator particles are a plurality of To form a co-suspension. In one such embodiment, at least 90% by volume of the first, second and third types of active agent particles exhibit an optical diameter of less than 7 μm and the total mass of suspended particles versus the first, second and third types. The ratio of the total mass of activator particles is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1.

  In another aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; and a metered dose inhaler Glycopyrrolate (any pharmaceutically acceptable salt, ester thereof) suspended in the suspension medium at a concentration sufficient to provide a glycopyrrolate delivery dose of about 15 μg to about 80 μg per actuation of Active agent particles, including isomers or solvates); the suspension at a concentration sufficient to provide a formoterol delivery dose of about 2 μg to about 10 μg per actuation of a metered dose inhaler. A second type of active agent particle comprising formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) suspended in a turbid medium; 1 of a metered dose inhaler Providing a budesonide delivery dose of about 30 μg to about 50 μg per actuation A third active agent particle comprising budesonide (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) suspended in the suspending medium at a sufficient concentration; A plurality of respirable suspension particles comprising a porous microstructure exhibiting a median optical diameter volume of 1.5 μm to about 10 μm, wherein the first, second and third types of activator particles are And associate with a plurality of suspended particles to form a co-suspension. In one such embodiment, at least 90% by volume of the first, second and third types of active agent particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first, second and third. The ratio of the total mass of seed activator particles is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1.

  In another aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; and a metered dose inhaler Of tiotropium (any pharmaceutically acceptable salt, ester, isomer thereof, or suspension thereof) suspended in the suspension medium at a concentration sufficient to provide about 5 μg to about 20 μg of tiotropium delivery dose per A first active agent particle comprising a solvate; and a concentration of about 2 μg to about 10 μg of formoterol delivered per actuation of a metered dose inhaler in the suspension medium at a concentration sufficient to provide A second active agent particle comprising suspended formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof); about 30 μg per actuation of a metered dose inhaler To provide a budesonide delivery dose of ~ 50 μg. A third active agent particle comprising budesonide (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) suspended in the suspension medium at a concentration of about 1.5; a plurality of respirable suspension particles comprising a porous microstructure exhibiting a median optical diameter volume of from about μm to about 10 μm, wherein the first, second and third types of activator particles include: It associates with the plurality of suspended particles to form a co-suspension. In one such embodiment, at least 90% by volume of the first, second and third types of active agent particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first, second and third. The ratio of the total mass of seed activator particles is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1.

  [0136] In another embodiment, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; Glycopyrrolate suspended in the suspension medium at a concentration sufficient to provide a glycopyrrolate delivery dose of about 15 μg to about 80 μg per actuation of the inhaler (any of its pharmaceutically acceptable) A first active agent particle comprising a salt, ester, isomer or solvate; and a concentration sufficient to provide a formoterol delivery dose of about 2 μg to about 10 μg per actuation of a metered dose inhaler A second active agent particle comprising formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) suspended in said suspending medium; Provides a mometasone delivery dose of about 20 μg to about 100 μg per actuation of the vessel A third active agent particle comprising mometasone (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) suspended in the suspending medium at a concentration sufficient for A plurality of respirable suspension particles comprising a perforated microstructure exhibiting a median optical diameter volume of about 1.5 μm to about 10 μm, wherein said first, second and third types of activator particles Associate with the plurality of suspended particles to form a co-suspension. In one such embodiment, at least 90% by volume of the first, second and third types of active agent particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first, second and third. The ratio of the total mass of seed activator particles is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1.

  In another aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; and a metered dose inhaler Of tiotropium (any pharmaceutically acceptable salt, ester, isomer thereof, or suspension thereof) suspended in the suspension medium at a concentration sufficient to provide about 5 μg to about 20 μg of tiotropium delivery dose per A first active agent particle comprising a solvate; and a concentration of about 2 μg to about 10 μg of formoterol delivered per actuation of a metered dose inhaler in the suspension medium at a concentration sufficient to provide A second active agent particle comprising suspended formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof); about 20 μg per actuation of a metered dose inhaler To provide a mometasone delivery dose of ~ 100 μg A third active agent particle comprising mometasone (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) suspended in the suspending medium at a concentration of about; A plurality of respirable suspended particles comprising a perforated microstructure exhibiting a median optical diameter volume of 1.5 μm to about 10 μm, wherein the first, second and third types of activator particles include: It associates with the plurality of suspended particles to form a co-suspension. In one such embodiment, at least 90% by volume of the first, second and third types of active agent particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first, second and third. The ratio of the total mass of seed activator particles is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1.

  In another aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; and a metered dose inhaler Glycopyrrolate (any pharmaceutically acceptable salt, ester thereof) suspended in the suspension medium at a concentration sufficient to provide a glycopyrrolate delivery dose of about 15 μg to about 80 μg per actuation of A first active agent particle comprising an A second active agent particle comprising formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) suspended in a turbid medium; and beclomethasone, budesonide, ciclesonide, flunisolide , Fluticasone, methyl A plurality of porous microstructures incorporating a corticosteroid selected from prednisolone, mometasone, prednisone and triamcinolone, including any pharmaceutically acceptable salt, ester, isomer or solvate thereof. Respirable suspended particles, wherein the suspended particles exhibit a median optical diameter volume of about 1.5 μm to about 10 μm and are associated with and co-suspended with the first and second types of activator particles. A turbid liquid is formed. In one such embodiment, at least 90% by volume of the first and second types of activator particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first and second types of activator particles. The total mass ratio is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1.

  In another aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; and a metered dose inhaler Glycopyrrolate (any pharmaceutically acceptable salt, ester thereof) suspended in the suspension medium at a concentration sufficient to provide a glycopyrrolate delivery dose of about 15 μg to about 80 μg per actuation of Active agent particles, including isomers or solvates); the suspension at a concentration sufficient to provide a formoterol delivery dose of about 2 μg to about 10 μg per actuation of a metered dose inhaler. A second active agent particle comprising formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) suspended in a turbid medium; and budesonide (any pharmaceutically acceptable salt thereof); An acceptable salt, ester, isomer or solvate A plurality of respirable suspended particles comprising a perforated microstructure that incorporates, wherein the suspended particles deliver about 30 μg to about 50 μg budesonide per actuation of a metered dose inhaler It contains sufficient budesonide to provide a dose, exhibits a median optical diameter volume of about 1.5 μm to about 10 μm, and associates with the first and second type of active agent particles to form a co-suspension. In one such embodiment, at least 90% by volume of the first and second types of activator particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first and second types of activator particles. The total mass ratio is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1.

  In another aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; and a metered dose inhaler Glycopyrrolate (any pharmaceutically acceptable salt, ester thereof) suspended in the suspension medium at a concentration sufficient to provide a glycopyrrolate delivery dose of about 15 μg to about 80 μg per actuation of Active agent particles, including isomers or solvates); the suspension at a concentration sufficient to provide a formoterol delivery dose of about 2 μg to about 10 μg per actuation of a metered dose inhaler. A second type of active agent particle comprising formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof) suspended in a turbid medium; and mometasone (any pharmaceutical thereof) An acceptable salt, ester, isomer or solvate A plurality of respirable suspended particles comprising a perforated microstructure incorporating a mometasone delivery dose of about 20 μg to about 100 μg per actuation of a metered dose inhaler With sufficient mometasone to exhibit a median optical diameter volume of about 1.5 μm to about 10 μm and associate with the first and second type of active agent particles to form a co-suspension. In one such embodiment, at least 90% by volume of the first and second types of activator particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first and second types of activator particles. The total mass ratio is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1.

  In another aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; and a metered dose inhaler Of tiotropium (any pharmaceutically acceptable salt, ester, isomer thereof, or suspension thereof) suspended in the suspension medium at a concentration sufficient to provide about 5 μg to about 20 μg of tiotropium delivery dose per A first active agent particle comprising a solvate; and a concentration of about 2 μg to about 10 μg of formoterol delivered per actuation of a metered dose inhaler in the suspension medium at a concentration sufficient to provide A second active agent particle comprising suspended formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof); beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylplutone A plurality of porous microstructures incorporating a corticosteroid selected from donisolone, mometasone, prednisone and triamcinolone, including any pharmaceutically acceptable salt, ester, isomer or solvate thereof. Respirable suspended particles, wherein the suspended particles exhibit a median optical diameter volume of about 1.5 μm to about 10 μm and are associated with and co-suspended with the first and second types of active agent particles. Form a liquid. In one such embodiment, at least 90% by volume of the first and second types of activator particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first and second types of activator particles. The total mass ratio is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1.

  In another aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; and a metered dose inhaler Of tiotropium (any pharmaceutically acceptable salt, ester, isomer thereof, or suspension thereof) suspended in the suspension medium at a concentration sufficient to provide about 5 μg to about 20 μg of tiotropium delivery dose per A first active agent particle comprising a solvate; and a concentration of about 2 μg to about 10 μg of formoterol delivered per actuation of a metered dose inhaler in the suspension medium at a concentration sufficient to provide A second active agent particle comprising suspended formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof); budesonide (any pharmaceutically acceptable salt thereof); Including salt, ester, isomer or solvate) A plurality of respirable suspended particles comprising a perforated microstructure incorporating a budesonide delivery dose of about 30 μg to about 50 μg per actuation of a metered dose inhaler. It contains sufficient budesonide to provide, exhibits a median optical diameter volume of about 1.5 μm to about 10 μm, and associates with the first and second type of active agent particles to form a co-suspension. In one such embodiment, at least 90% by volume of the first and second types of activator particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first and second types of activator particles. The total mass ratio is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1.

  In another aspect, a co-suspension composition deliverable from a metered dose inhaler according to the present description comprises: a suspension medium comprising a pharmaceutically acceptable HFA propellant; and a metered dose inhaler Of tiotropium (any pharmaceutically acceptable salt, ester, isomer thereof, or suspension thereof) suspended in the suspension medium at a concentration sufficient to provide about 5 μg to about 20 μg of tiotropium delivery dose per A first active agent particle comprising a solvate; and a concentration of about 2 μg to about 10 μg of formoterol delivered per actuation of a metered dose inhaler in the suspension medium at a concentration sufficient to provide A second active agent particle comprising suspended formoterol (including any pharmaceutically acceptable salt, ester, isomer or solvate thereof); mometasone (any pharmaceutically acceptable salt thereof); Including salt, ester, isomer or solvate) A plurality of respirable suspension particles comprising a perforated microstructure that incorporates a mometasone delivery dose of about 20 μg to about 100 μg per actuation of a metered dose inhaler. It contains sufficient mometasone to provide, exhibits a median optical diameter volume of about 1.5 μm to about 10 μm, and associates with the first and second type of active agent particles to form a co-suspension. In one such embodiment, at least 90% by volume of the first and second types of activator particles exhibit an optical diameter of less than 7 μm and the total mass of the suspended particles versus the first and second types of activator particles. The total mass ratio is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1.

III. Metered Spray Inhaler Systems As described with respect to the methods provided herein, the co-suspension compositions disclosed herein can be used in MDI systems. An MDI is configured to deliver a specific amount of a medicament in aerosol form. In one aspect, the MDI system comprises a can filled with a pressurized liquid phase formulation placed in an actuator formed with a mouthpiece. The MDI system can include a formulation described herein comprising a suspending medium, at least one active agent particle, and at least one suspended particle. The cans used in the MDI can be of any suitable configuration, and in one exemplary embodiment, the can volume can range from about 5 ml to about 25 ml (eg, a can having a volume of 19 ml). . After shaking the instrument, the mouthpiece is inserted into the patient's mouth (between lips and teeth). The patient usually exhales a large amount to empty the lungs and then slowly takes a deep breath while operating the cartridge.

  Inside the exemplary cartridge is a metering valve with a metering chamber capable of holding a defined volume of formulation (eg 63 μl, or any other suitable volume available with commercially available metering valves). is there. This formulation is released into the expansion chamber at the distal end of the valve shaft upon actuation. The actuator may include a port with an actuator nozzle for holding the can and receiving the valve shaft of the metering valve. When activated, a certain amount of formulation moves into the expansion chamber, out of the working nozzle and becomes a high speed spray that is inhaled into the patient's lungs.

IV. Methods Provided herein are methods for formulating a pharmaceutical composition for respiratory delivery of at least two active agents. In one aspect, the method includes providing a suspending medium, one or more active agent particles, and one or more suspended particles, and combining such components, as described herein. The activator particles associate with the suspended particles to form a composition co-located with the suspended particles in the suspending medium to form a co-suspension. In one such embodiment, the association between the active agent particles and the suspended particles is such that they do not separate due to different buoyancy in the propellant. As will be appreciated, the method of formulating a pharmaceutical composition described herein can include providing two or more active agent particles in combination with one or more suspended particles. In a further aspect, the method can include providing two or more suspended particles in combination with two or more active agent particles to form a co-suspension. In yet other embodiments, one or more active agent particles can be combined with one or more suspended particles described herein. In certain embodiments, the active agent material included in the active agent particles is selected from one or more of a LABA active agent, a LAMA active agent, or a corticosteroid active agent. In certain embodiments, the active agent particles consist essentially of the active agent material and are free of additional excipients, adjuvants, stabilizers, and the like.

  In a particular aspect of a method for providing a stabilized composition of a combination of two or more active agents, the present disclosure provides a method for inhibiting solution-mediated transfer of an active agent in a pharmaceutical composition for pulmonary delivery. In one embodiment, a suspending medium as described herein (such as a suspending medium formed by an HFA propellant) is obtained. Suspended particles are also obtained or prepared as described herein. Active agent particles are also obtained, the suspension medium, the suspension particles and the active agent particles are mixed, and the active agent particles associate with the suspension particles and are suspended in a continuous phase formed by the suspension medium. To form a co-suspension located in the same location. When compared to active agent particles contained in the same suspension medium in the absence of suspended particles, the co-suspension according to the present description is more resistant to solution-mediated phase transitions leading to irreversible crystal aggregation. Therefore, it was found that there is a possibility of improving stability and administration uniformity.

  In a further aspect, a method of forming a stabilized composition comprising two or more active agents for pulmonary delivery comprises maintaining the FPF and / or FPD of the composition until the MDI can is empty. In a particular embodiment of the method for maintaining FPF and / or FPD provided by a pharmaceutical composition for pulmonary delivery, the FPD and / or FPF is reconstituted with the first FPD and / or FPF, respectively, until the MDI can is empty. A respirable co-suspension as described herein is provided that can be maintained within ± 20%, ± 10% or even ± 5%. Such performance can be achieved when two or more active agents are incorporated into the co-suspension and even after the co-suspension is exposed to accelerated degradation conditions. In one embodiment, a suspending medium as described herein (such as a suspending medium formed by an HFA propellant) is obtained. Suspended particles are also obtained or prepared as described herein. Active agent particles are also obtained, and the suspension medium, the suspension particles, and the active agent particles are mixed so that the active agent particles associate with the suspension particles and are co-located with the suspension particles in the same location. A turbid liquid is formed. Even after exposing such a composition to one or more temperature cycling events, the co-suspension is within ± 20% of each value measured before exposing the composition to multiple temperature cycling events, Maintain FPD or FPF within ± 10% or even within ± 5%.

  Disclosed are methods for preparing MDI for respiratory delivery of two or more active agents. In certain aspects, such methods can include filling the cans described herein with active agent particles and suspended particles. An actuator valve can be attached to the end of the can to seal the can. The actuator valve can be configured to dispense a metered amount of active agent contained in the co-suspension composition per actuation of the MDI. The can can contain a pharmaceutically acceptable suspending medium (such as a propellant as described herein) so that the active and suspended particles are in the suspending medium. Provide a stable co-suspension.

  In methods involving respiratory delivery of two or more active agents using the compositions described herein, the compositions can be delivered by MDI. Thus, in certain embodiments of such methods, an MDI loaded with the compositions described herein is obtained and two or more active agents are administered to the patient by respiratory delivery via actuation of the MDI. . For example, in one embodiment involving pulmonary delivery of two or more active agents, the mouthpiece is inserted into the patient's mouth (between the lips and teeth) after shaking the MDI device. The patient typically exhales a large amount to empty the lungs and then slowly and deeply breathes while the MDI cartridge is activated. When activated, a certain amount of formulation moves into the expansion chamber and out of the actuator nozzle to become a high speed spray that is inhaled into the patient's lungs. In one aspect, the amount of each active agent delivered before the MDI can is emptied does not exceed more than 30% of the average delivery dose (not more than 30% greater than) and is less than 30% of the average delivery dose. (Not less than 30% less than). Accordingly, a method of achieving the desired DDU of two or more active agents delivered from MDI is also provided. In such embodiments, the method includes, for example, ± 30% or better DDU, ± 25% or better DDU, and ± until the MDI can to which the co-suspension composition is delivered is empty. Achieving a DDU for each of two or more active agents delivered from the MDI, selected from 20% or better DDU.

  Provided herein are methods for treating a patient suffering from an inflammatory or obstructive pulmonary disease or condition. In certain embodiments, such methods include pulmonary delivery of the pharmaceutical compositions described herein, and in certain such embodiments, pulmonary administration of the pharmaceutical compositions is performed using MDI. Is achieved. The disease or condition to be treated can be selected from any inflammatory or obstructive pulmonary disease or condition that responds, for example, to administration of an active agent described herein. In some embodiments, the active agent combination comprises at least one active agent selected from a LAMA active agent, a LABA active agent, or a corticosteroid active agent. In certain embodiments, the pharmaceutical compositions described herein include the following: asthma, COPD, exacerbated airway hyperresponsiveness resulting from other medications, allergic rhinitis, sinusitis, pulmonary vasoconstriction, Inflammation, allergies, respiratory disorders, respiratory distress syndrome, pulmonary hypertension, pulmonary vasoconstriction, emphysema, and any other respiratory disease, symptom that can respond to administration of combinations of active agents described herein, It can be used in the treatment of diseases or disorders selected from traits, genotypes or phenotypes. In certain aspects, the pharmaceutical compositions described herein can be used in the treatment of pulmonary inflammation and obstruction associated with cystic fibrosis.

Furthermore, the pharmaceutical composition according to the present description delivered from MDI provides desirable pharmacodynamic (PD) performance. In certain embodiments, pulmonary capacity is rapidly improved significantly upon pulmonary delivery of the pharmaceutical compositions described herein. This can be characterized by an improvement in the patient's forced expiratory volume in one second (FEV ₁ ). For example, in certain embodiments, methods are provided to achieve a clinically significant increase in FEV ₁ , wherein such methods are co-suspension compositions comprising two or more active agents, and Providing a co-suspension composition wherein at least one of the active agents is selected from a LABA activator, LAMA activator or corticosteroid activator as described herein; and Administration by MDI to patients suffering from lung inflammation or obstruction. In one such embodiment, the active agent included in the composition comprises a combination of a LABA active agent and a LAMA active agent, a combination of a LABA active agent and a corticosteroid active agent, a LAMA active agent and a corticosteroid active. And a combination selected from one of a combination of a LABA active agent, a LAMA active agent and a corticosteroid active agent. For purposes of this disclosure, a clinically significant increase in FEV ₁ is any increase of 100 ml or greater, and in certain embodiments of the methods described herein, the composition according to the present description When administered to a patient, FEV ₁ increases clinically significantly within 1 hour. In other such embodiments, the method of administering a composition described herein to a patient by MDI results in a clinically significant increase in FEV1 within 0.5 hours.

In a further aspect, 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 that achieve FEV ₁ of 150 ml or more within a period selected from within 0.5 hours, within 1 hour, and within 1.5 hours. In other embodiments, the methods described herein include methods that achieve FEV ₁ of 200 ml or more within a period selected from within 0.5 hours, within 1 hour, within 1.5 hours, and within 2 hours. In yet other such embodiments, the methods described herein comprise a method of achieving FEV ₁ of 250 ml or more within a period selected from within 0.5 hours, within 1 hour, within 1.5 hours, and within 2 hours. Including. In yet another such embodiment, the method described herein comprises a method of achieving FEV ₁ of 300 ml or more within a period selected from within 0.5 hours, within 1 hour, within 1.5 hours, and within 2 hours. Including. In yet other such embodiments, the methods described herein achieve FEV ₁ of 350 ml or more within a period selected from within 0.5 hours, within 1 hour, within 1.5 hours, and within 2 hours. including. Further, in such embodiments, the active agent included in the composition comprises a combination of a LABA active agent and a LAMA active agent, a combination of a LABA active agent and a corticosteroid active agent, a LAMA active agent and a corticosteroid active. And a combination selected from one of a combination of an LABA active agent, a LAMA active agent and a corticosteroid active agent, wherein the composition is delivered to the patient by MDI.

In yet a further aspect, a method of achieving and maintaining a clinically significant increase in FEV ₁ is provided. In certain embodiments, when a single dose of active agent combination formulated in the form of a composition described herein is administered to a patient by MDI, a clinically significant increase in FEV ₁ is 0.5 hours. Within 1 hour and 1.5 hours, and a clinically significant increase in FEV ₁ is maintained up to 12 hours or more. In certain such embodiments, the increase in FEV ₁ may be selected from an increase of 150 ml or more, 200 ml or more, 250 ml or more, 300 ml or more, and 350 ml or more, and the increase in FEV ₁ may be up to 4 hours, up to 6 hours, Maintained clinically significant over a period selected from up to 8 hours, up to 10 hours and up to 12 hours or more. In certain such embodiments, the active agent included in the composition comprises a combination of a LABA active agent and a LAMA active agent, a combination of a LABA active agent and a corticosteroid active agent, a LAMA active agent and a corticosteroid A combination comprising an active agent and a combination selected from one of a combination of an LABA active agent, a LAMA active agent and a corticosteroid active agent, wherein the composition is delivered to the patient by MDI .

The compositions, systems and methods described herein are not only suitable for achieving the desired pharmacodynamic outcome in a short period of time, but also achieve such results in a high percentage in patients. Will. For example, provided herein is a method of achieving an increase in FEV ₁ of 10% or more in 50% or more of patients suffering from lung inflammation or obstruction. For example, in certain embodiments, the method of achieving a 10% or greater increase in FEV _{1 in} a patient comprises selecting at least one active agent from a LABA active agent, a LAMA active agent, and a corticosteroid active agent as described herein. Providing a co-suspension composition comprising a combination of active agents to be administered, and administering such a composition by MDI to a patient suffering from pulmonary inflammation or obstruction. In certain such embodiments, administration of the composition causes 10% or more FEV in a period selected from within 0.5 hours, within 1 hour, within 1.5 hours, and 2 hours in 50% or more patients. ₁ increases. In other such embodiments, the composition is administered to at least 10% in 60% or more patients within a period selected from within 0.5 hours, within 1 hour, within 1.5 hours, and within 2 hours. FEV ₁ increases. In still other such embodiments, administration of the composition results in 10% in 70% or more patients within a period selected from within 0.5 hours, within 1 hour, within 1.5 hours, and within 2 hours. As a result, FEV ₁ increases. In yet other such embodiments, administration of the composition results in 10% in 80% or more patients within a period selected from within 0.5 hours, within 1 hour, within 1.5 hours, and within 2 hours. As a result, FEV ₁ increases. In certain such embodiments, the active agent included in the composition comprises a combination of a LABA active agent and a LAMA active agent, a combination of a LABA active agent and a corticosteroid active agent, a LAMA active agent and a corticosteroid A combination comprising an active agent and a combination selected from one of a combination of an LABA active agent, a LAMA active agent and a corticosteroid active agent, wherein the composition is delivered to the patient by MDI.

In certain embodiments, the methods described herein facilitate the treatment of patients suffering from lung inflammation or obstruction. Here, such methods include providing a co-suspension composition comprising a combination of active agents described herein and such patients by MDI to patients suffering from pulmonary inflammation or obstruction. By administering the composition by MDI, the patient may receive at least a 200 ml increase from the FEV ₁ baseline or a total increase of FEV ₁ of at least 150 ml of FEV ₁ . Any increase of 12% or more from the baseline. In certain such embodiments, FEV ₁ baseline is administered within a period selected from within 1 hour, within 1.5 hours, within 2 hours, and within 2.5 hours in more than 50% of patients upon administration of the composition. From at least a 200 ml increase or a total increase of at least 150 ml of FEV ₁ plus a 12% increase from the FEV ₁ baseline. In other such embodiments, the FEV ₁ baseline is administered within a period selected from within 1 hour, within 1.5 hours, within 2 hours, and within 2.5 hours in more than 60% of patients upon administration of the composition. From at least a 200 ml increase or a total increase of at least 150 ml of FEV ₁ plus a 12% increase from the FEV ₁ baseline. In still other such embodiments, the composition is administered and the FEV ₁ base is administered in a period selected from within 1.5 hours, within 2 hours, within 2.5 hours, and within 3 hours in 70% or more patients. There will be either an increase of at least 200 ml from the line or a 12% increase from the baseline of FEV ₁ in addition to a total increase of FEV ₁ of at least 150 ml. In yet other such embodiments, upon administration of the composition, the FEV ₁ base is administered in a period selected from within 1.5 hours, within 2 hours, within 2.5 hours, and within 3 hours in more than 80% of patients. There will be either an increase of at least 200 ml from the line or a 12% increase from the baseline of FEV ₁ in addition to a total increase of FEV ₁ of at least 150 ml. In certain such embodiments, the active agent included in the composition comprises a combination of a LABA active agent and a LAMA active agent, a combination of a LABA active agent and a corticosteroid active agent, a LAMA active agent and a corticosteroid A combination comprising an active agent and a combination selected from one of a combination of an LABA active agent, a LAMA active agent and a corticosteroid active agent, wherein the composition is delivered to the patient by MDI .

In some embodiments, the improvement provided by a composition that delivers only a single active agent, in a manner that achieves and maintains a clinically significant increase in FEV ₁ as described herein, is in contrast to FEV 1. show significant improvement in _1, an increase of FEV _1. For purposes of comparing only a single active agent to the FEV ₁ performance of the compositions described herein, a significant improvement in FEV ₁ is an improvement of 60 ml or more. For example, in certain embodiments, a method of achieving a significant improvement in FEV ₁ relative to the improvement provided by a composition that delivers only a single active agent, wherein at least one active agent is described herein. Providing a co-suspension composition as described herein comprising a combination of active ingredients selected from LABA, LAMA and corticosteroid active agents; and MDI for patients suffering from lung inflammation or obstruction Administering such a composition. In certain such embodiments, administering the co-suspension composition has at least 70 ml of FEV ₁ AUC ₀₋ compared to FEV ₁ AUC _0-12 achieved by the composition delivering a single active agent. ₁₂ improvements. In other such embodiments, administration of the co-suspension composition has at least 80 ml of FEV ₁ AUC ₀₋ compared to FEV ₁ AUC _0-12 achieved by the composition delivering a single active agent. ₁₂ improvements. In yet other such embodiments, administration of the co-suspension composition has at least 90 ml of FEV ₁ AUC ₀ compared to FEV ₁ AUC _0-12 achieved by the composition delivering a single active agent. _-12 improvement.

In other embodiments, the method for achieving a significant improvement in FEV ₁ relative to the improvement achieved by a composition that delivers a single active agent is a method in which at least one active agent is LABA as described herein, Providing a co-suspension composition as described herein comprising a combination of active agents selected from LAMA and corticosteroid active agents; and MDI for patients suffering from lung inflammation or obstruction Administering such a composition, and by such administration, the peak change in FEV ₁ (peak FEV ₁ ) compared to the peak FEV ₁ achieved by the composition delivering a single active agent Improves significantly. In certain such embodiments, the administration of the co-suspension compositions described herein, as compared to peak FEV ₁ which is achieved by a composition for administration of a single active agent, the peak FEV ₁ is Improve at least 70ml. In certain such embodiments, the administration of the co-suspension compositions described herein, as compared to peak FEV ₁ which is achieved by a composition for administration of a single active agent, the peak FEV ₁ is Improve at least 80ml. In certain such embodiments, the administration of the co-suspension compositions described herein, as compared to peak FEV ₁ which is achieved by a composition for administration of a single active agent, the peak FEV ₁ is Improve at least 90ml.

  Also provided are methods that provide a clinically significant increase in inspiratory capacity (IC) in patients suffering from lung inflammation or obstruction. As used herein, IC is defined as the maximum amount of gas that can be taken into the lungs upon full inhalation after successfully exhaling, and a clinically significant increase in IC is defined as Any increase over 70ml. For example, in certain embodiments, the methods for improving IC described herein include a combination of active agents, wherein at least one active agent is selected from the LABA, LAMA, and corticosteroid active agents described herein. Providing a co-suspension composition as described herein comprising: administering such composition by MDI to a patient suffering from pulmonary inflammation or obstruction, wherein the composition comprises IC increases by more than 70 ml by administration of the product. In such specific embodiments, embodiments according to the present description increase the IC by 100 ml or more. In such other embodiments, administration of a composition according to the present description results in an increase of IC of 200 ml or more. In yet other embodiments, administration of the composition according to the present description increases the IC by 300 ml or more, and in yet other embodiments, administration of the composition according to the present description increases the IC by 350 ml or more. In a specific embodiment, the increase in IC is rapid. For example, in each of the methods described, a clinically significant increase or increase in IC selected from 100 ml or more, 200 ml or more, 300 ml or more, or 350 ml or more is selected from within 1 hour and within 2 hours. Can happen with the patient in time.

  The methods of increasing IC described herein are not only useful for rapidly and clinically significantly increasing IC over a short period of time, but also providing a clinically significant increase in IC over time. It is also useful to maintain. For example, as highlighted by the clinical results shown in Example 12, a clinically significant increase in IC provided by the methods described herein is experienced by the patient rapidly after administration, with an increase in IC Remain clinically significant for up to 12 hours or longer after administration, and the increase in IC remains clinically significant even after prolonged administration (e.g., multiple consecutive days of administration). is there.

  Furthermore, compositions according to the present description provide a more significant increase in IC than that provided by compositions that deliver only a single active agent. In embodiments of the methods described herein for enhancing IC, administration of the co-suspension composition described herein is at least 70 ml greater than the increase in IC provided by the composition delivering only a single active agent. Provides high IC increase. In one such aspect, an increase in IC provided by administering a co-suspension composition described herein is an increase in IC provided by a composition that delivers only a single active agent. Is at least 100ml higher. In another such aspect, the increase in IC provided by administering the co-suspension composition described herein is provided by a composition that delivers only a single active agent. At least 125ml higher than the increase in IC.

In some embodiments, the methods described herein for achieving the desired pharmacodynamic effect are characterized by the delivery of a relatively small amount of active agent. In certain such embodiments, the methods described herein for achieving a clinically significant increase in, for example, FEV ₁ , include a combination of glycopyrrolate and formoterol activator as described herein. Administering a co-suspension, wherein the co-suspension is administered to a patient by metered dose inhaler up to twice per day, each dose being no more than 150 μg of glycopyrrole. The patient is given a total delivered dose of rate and a total delivered dose of only 12 μg formoterol. In such other embodiments, the methods described herein for achieving a clinically significant increase in FEV ₁ include a combination described herein comprising a combination of glycopyrrolate and formoterol activator. Administering the suspension, wherein the co-suspension is administered to the patient by metered dose inhaler up to 2 times per day, each administration being a total delivery dose of only 100 μg glycopyrrolate and The patient is administered a total delivery dose of only 12 μg formoterol. In such other embodiments, the methods described herein for achieving a clinically significant increase in FEV ₁ include a combination described herein comprising a combination of glycopyrrolate and formoterol activator. Administering the suspension, wherein the co-suspension is administered to the patient by metered dose inhaler up to two times per day, each administration comprising a total delivery dose of only 80 μg glycopyrrolate and The patient is administered a total delivery dose of only 12 μg formoterol. In yet another aspect, the method described herein for achieving a clinically significant increase in FEV ₁ includes a co-suspension as described herein comprising a combination of glycopyrrolate and formoterol activator. Administering the liquid, wherein the co-suspension is administered to the patient by metered dose inhaler up to twice per day, each dose being only 50 μg glycopyrrolate total delivery dose and only 12 μg The patient is administered a total delivery dose of formoterol.

  In some embodiments, a method of achieving a clinically significant increase in the IC described herein includes administering the co-suspension composition described herein to a patient via a metered dose inhaler. Wherein the co-suspension comprises glycopyrrolate and formoterol activator, the co-suspension is administered to the patient by metered dose inhaler up to twice per day, each dose of only 150 μg The patient is administered a total delivery dose of glycopyrrolate and a total delivery dose of only 12 μg formoterol. In certain such embodiments, for example, the methods described herein for achieving a clinically significant increase in IC include a combination described herein comprising a combination of glycopyrrolate and formoterol activator. Administering the suspension, wherein the co-suspension is administered to the patient by metered dose inhaler up to 2 times per day, each dose being only 100 μg glycopyrrolate total delivery dose and only A total delivery dose of 12 μg formoterol is administered to the patient. In such other embodiments, the methods described herein for achieving a clinically significant increase in IC comprise a co-suspension as described herein comprising a combination of glycopyrrolate and formoterol activator. Administering the solution, wherein the co-suspension is administered to the patient by metered dose inhaler up to 2 times per day, each dose being only 80 μg glycopyrrolate total delivery dose and only 12 μg The patient is administered a total delivery dose of formoterol. In yet another aspect, a method described herein for achieving a clinically significant increase in IC comprises a co-suspension described herein comprising a combination of glycopyrrolate and formoterol activator. Wherein the co-suspension is administered to the patient by metered dose inhaler up to 2 times per day, each dose being only 50 μg glycopyrrolate total delivery dose and only 12 μg formoterol The total delivery dose of is delivered to the patient.

Compositions provided and delivered by the methods described herein can include co-suspension compositions comprising any combination of active agents described herein. For example, in certain embodiments, the methods described herein for achieving a clinically significant increase in FEV ₁ or IC provide a co-suspension composition comprising two or more active agents; Wherein at least one of such active agents is selected from the LABA, LAMA or corticosteroid active agents described herein, and such patients may suffer from pulmonary inflammation or obstruction due to MDI. Administering a composition. In one such embodiment, the active agent included in the co-suspension composition comprises a combination of LABA and LAMA active agent, a combination of LABA and corticosteroid active agent, a combination of LAMA and corticosteroid active agent, And a composition selected from one of the combinations with LABA, LAMA and a corticosteroid activator. In specific embodiments of the methods described herein, the co-suspension composition provided and administered is any of the specific co-suspension compositions described in detail herein. It can be.

  The specific examples contained herein are for illustrative purposes only and should not be considered limiting to the present disclosure. Moreover, while the compositions, systems and methods disclosed herein have been described in connection with specific embodiments thereof, many details have been set forth for purposes of illustration, those skilled in the art will It will be apparent that the invention is amenable to additional aspects and that certain of the details described herein may be changed without departing from the basic principles of the invention. Any active agents and reagents used in the following examples are either commercially available or can be prepared by standard literature procedures by one skilled in the art of organic synthesis. The entire contents of all publications, patents and patent applications referred to herein are hereby incorporated by reference.

Example 1
Exemplary co-suspension compositions described herein were prepared and evaluated. The composition contained a combination of a glycopyrrolate (GP) activator and a formoterol fumarate (FF) activator. GP was present in the propellant as finely divided crystalline active agent particles. The GP was co-suspended with the spray-dried suspended particles containing FF placed in the material forming the suspended particles. To accomplish this, FF was dissolved in the raw material used to produce lipid-based suspended particles.

  GP activator particles were formed by micronizing glycopyrrolate using a jet mill. The particle size distribution of the glycopyrrolate activator particles was quantified by laser diffraction in a Fraunhofer diffraction mode using a laser diffraction particle size analyzer equipped with a dry powder dispenser (eg Sympatec GmbH, Clauusthal-Zellerfeld, Germany). 50% by volume of 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 produced as follows. Prepare 654 mL of a phospholipid stabilized PFOB (perfluorooctyl bromide) fluorocarbon in water emulsion; 26.5 g of phospholipid, DSPC ((1,2-disteroyl-sn-glycero-3- Phosphocholine) and 2.4 g of calcium chloride were homogenized in 276 mL of hot water (80 ° C.) using a high shear mixer; 142 mL of PFOB was added slowly during the homogenization. The emulsion was further homogenized using a high pressure homogenizer (Model C3, Avestin, Ottawa, Canada) at a pressure of up to 170 MPa for 5 passes, 552 mg of FF dissolved in 273 mL of warm water (50 ° C.) Was mixed with the emulsion using a high shear mixer, which was then spray dried under the following spray drying conditions: inlet temperature 95 ° C .; outlet temperature 68 ° C .; emulsion feed rate 2.4 ml / min; 498L / min was spray dried in a nitrogen using. Final mass fraction of formoterol spray dry powder was 2%.

  A second lot of FF-containing suspended particles was produced in a similar manner. The mass fraction of FF in the spray-dried powder was 1% for this lot. The third lot of suspended particles was produced without using 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.

  Prepare MDI containing FF, GP or both by weighing the target mass of activator particles and suspended particles into a 19 mL volume aluminum fluoroethylene polymer (FEP) coated aluminum can (Presspart, Blackburn, UK) did. This can was crimp sealed with a 63 μl valve (# BK357, Bespak, King's Lynn, UK) and 12.4 g of HFA134a (1,1,1,2-tetrafluoroethane) (Ineos Flour, Lyndhurst, UK). The resulting suspension concentration and target delivery dose (assuming 20% is deposited on the actuator) are shown in Table 1a for three different configurations (Configurations 1A-1C). After injection of the propellant, the can was sonicated for 15 seconds and agitated for 30 minutes on a wrist action shaker. The can was fitted with a polypropylene actuator (# BK636, Bespak, King's Lynn, UK) with a 0.3 mm orifice.

  The filled MDI was refrigerated at 5 ° C with two different conditions: without wrapping and at room temperature / 60% RH at 25 ° C controlled with foil wrapping. And stored. Aerosol performance and delivery dose uniformity studies were performed at different time points. Aerosol performance was examined after manufacture according to USP <601> (US Pharmacopoeia Monograph 601). A Next Generation Impactor (NGI) operating at a flow rate of 30 l / min was used to measure the particle size distribution. A sample can was placed in the actuator and two empty actuations and two additional priming actuations were performed. Five working minutes were collected in NGI with USP throat. Valves, actuators, throats, NGI cups, stages and filters were rinsed with volumetric and dispensed solvent. Sample solutions were assayed using drug specific chromatography methods. The total fraction from stage 3 to the filter was used to define the fine particle fraction. As described by USP <601>, a dose uniformity test by use test was performed using a dose uniformity sampling device. The inhaler was installed as described above and the priming work was performed. Two working minutes were collected and assayed at the beginning, middle and end of use.

  No trend was observed in aerosol performance or delivery dose uniformity over the duration of the study (3 months) or as a function of storage temperature. Therefore, all aerosol performance test results were pooled. Table 1b lists the average performance of the different configurations. The fine particle dose is the sum of the mass recovered on the filter from stage 3 of the impactor and is normalized by the metered dose. The average aerosol performance for all three configurations was comparable.

  Both active agents of this combination product were tested for dose content uniformity over the life of the can. 1 and 2 show the ex-actuator dose for configurations 1A and 1B, normalized by the actual metered dose of the can, respectively. Assuming 20% deposit on the actuator, the target dose exiting the actuator for both active agents was 80%. Individual FF doses and GP doses are represented by dots and triangles, respectively. The solid line represents the average formoterol dose and the dashed line represents the average glycopyrrolate dose. Figures 3 and 4 show the normalized dose ratio exiting the actuator for configurations 1A and 1B, respectively. The results suggest that the dose ratio remained constant throughout the life of the can. Furthermore, the dose ratio variability is much lower than that of the individual doses, indicating that a co-suspension with a consistent carrier to active agent ratio was formed and maintained throughout the life of the container. ing.

  The result is that when formulated in accordance with the disclosure provided herein, a co-suspension of the combination product is formed using suspended particles containing one of the active pharmaceutical ingredients (in this case, FF). Which indicates that. The ratio of suspended particles to active agent particles can be adjusted to achieve target dose content uniformity while maintaining similar aerosol performance.

Example 2
MDI containing FF, GP or both were prepared at target concentrations of 2.4 μg and 18 μg per actuation for FF and GP, respectively. When the GP activator is micronized, d ₁₀ , d ₅₀ and d ₉₀ are obtained, respectively, as measured in laser diffraction as described in Example 1, with spans of 0.6 μm, 1.7 μm, 3.6 μm and 1.9 μm. Met. FF is incorporated in the spray drying of suspended particles, 2% FF, 91.5 percent DSPC and 6.5% was prepared as described in Example 1 with the composition of CaCl _2. GP, FF, and GP + FF MDIs were prepared by weighing target masses of activator particles and suspended particles into a 19 ml volume of fluoroethylene polymer (FEP) coated aluminum cans (Presspart, Blackburn, UK). The can was crimp sealed with a 50 μl valve (# BK357, Bespak, King's Lynn, UK) and 10.2 g of HFA134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst) by overpressure through the valve shaft , UK). After injecting the propellant, the can was sonicated for 15 seconds and stirred on a wrist action shaker for 30 minutes. A polypropylene actuator (# BK636, Bespak, King's Lynn, UK) with a 0.3 mm orifice was attached to the can.

  The long-term aerosol stability and delivery characteristics of MDI compositions were evaluated. In particular, the aerosol particle size distribution and delivery dose characteristics of the compositions were evaluated according to USP <601> as described in Example 1 under various conditions, optionally over a period extended to up to 12 months. For example, as shown in FIG. 5, the delivery dose uniformity provided by the composition prepared according to Example 1 is that the MDI is stored after storage of the composition at 5 ° C. for 12 months or in an aluminum foil pouch. For samples with minimal water intrusion into the can (ie “protected storage”), even after 4.5 months at 25 ° C and 60% relative humidity (RH), Virtually maintained.

  The aerosol performance of such compositions was also evaluated through unprotected storage conditions extending up to 12 months and protected storage conditions extending up to 6 months. As shown in FIG. 6, the particle size distribution of GP and FF provided by this co-suspension composition is 12 months after protected storage at 5 ° C. and unprotected at 25 ° C. and 60% RH. It was substantially maintained after 6 months at storage conditions. As shown in FIG. 7, even under stressed conditions (40 ° C., 75% RH), the composition shows noticeable degradation in the particle size distribution of GP and FF delivered from a metered dose inhaler after 6 months. Not shown.

  Suspensions containing only a single active agent to assess whether combining GP and FF within a single formulation will degrade aerosol properties compared to compositions containing a single active agent Compared with the liquid composition, the aerosol properties of the co-suspension composition were investigated.

  As can be seen in FIG. 8, the aerosol performance of the combined co-suspension composition comprising both the GP activator and the FF activator is achieved by the suspension composition comprising either GP or FF alone. The performance was not different. This indicates that the aerosol properties of the individual active agents are substantially the same when obtained from a single component co-suspension or a two component combination co-suspension.

Example 3
The pharmacokinetics and safety of a metered dose inhaler in combination co-suspension containing glycopyrrolate and formoterol fumarate were evaluated in clinical trials. This clinical trial is a single-center, randomized, double-blind, single-dose, four-period, four-treatment treatment used to evaluate four inhalation therapies administered by MDI It was a crossover test. Four treatments consisted of formoterol fumarate (FF) inhalation aerosol, glycopyrrolate (GP) inhalation aerosol, GP + FF inhalation aerosol, and continuous delivery to deliver FF inhalation aerosol immediately following GP inhalation aerosol. Included. GP + FF inhalation aerosols, and FF inhalation aerosols and GP inhalation aerosols were prepared as described in Example 2. In addition, GP + FF inhalation aerosols are termed “fixed” combinations of GP and FF, and procedures requiring continuous delivery to deliver FF inhalation aerosols immediately following GP inhalation aerosols are “loose” We named it the “loose combination”.

  In the trial, subjects were randomized and assigned to one of four treatment sequences. Each treatment sequence included all four test treatments. Each subject received four single dose treatments 7-21 days apart. Sixteen subjects were enrolled and analyzed for safety. Three subjects were excluded from the PK analysis as a result of not taking one or more of the four therapeutic agents, and were further unassessable due to administration errors resulting from inadequate inhalation techniques, Two subjects were excluded from the PK analysis.

  The GP + FF inhalation aerosol was administered to provide each subject with a 72 μg dose of GP and a 9.6 μg dose of FF (4 actuations, 18 μg GP and 2.4 μg FF per actuation). The GP inhalation aerosol was administered to provide each subject with a 72 μg dose of GP (4 actuations, 18 μg GP per actuation). The FF inhalation aerosol was administered to provide each subject with a 9.6 μg dose of FF (4 actuations, 2.4 μg FF per actuation). For the purpose of blinding, four working placebo MDIs were administered before each of the three previous therapeutic agents. A loose combination of GP inhalation aerosol followed by FF inhalation aerosol was given to each subject with 72 μg GP and 9.6 μg FF (4 actuations, 18 μg GP per actuation followed by 4 additional actuations, 1 actuation. Per dose of 2.4 μg FF).

  Both the loose and fixed combinations of GP and FF are safe and well tolerated, and the fixed combination has a safety profile similar to that observed for the other three treatments evaluated in the trial. Indicated. Blood samples were quantified for GP and FF plasma concentrations prior to administration and at 2, 5, 15, and 30 minutes and 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 12 hours after administration. To collect and use this value to calculate various PK parameters. The plasma concentration time profiles for both GP and FF over a 12 hour period immediately after administration are shown in FIG. As can be seen in FIG. 9, when GP and FF are administered from a fixed combination, the plasma concentrations of GP and FF after administration result comparable to the plasma concentrations obtained from administration of a loose combination of GP and FF. It was. As mentioned in the in-vitro delivery dose and particle size distribution performance described in Example 2, for the combination GP + FF inhalation aerosol, no combination effect was observed in-vivo.

Example 4
An exemplary two-part co-suspension composition according to the present description was made and a metered dose inhaler incorporating the composition was prepared. The composition contained a combination of glycopyrrolate (GP) and formoterol fumarate (FF), each supplied as a finely divided crystalline material. A combination crystalline co-suspension MDI was prepared by semi-automatic suspension filling. This two-component co-suspension is two microcrystalline active pharmaceutical ingredients (also called “APIs”, or “API” in the singular) co-suspended with suspended particles in HFA134a propellant. It consisted of a combination of GP and FF. The two dose co-suspension was formulated to deliver a delivery dose of 18 μg GP per actuation and 4.8 μg FF per actuation. In the preparation of a two-part co-suspension composition, in certain compositions, the FF API material used is labeled as “coarse” and in other compositions, the FF API material used is Displayed as “fine”. Whether the co-suspension composition incorporates coarse FF or fine FF, the composition was formulated to deliver a delivery FF dose of 4.8 μg per actuation. The particle size characteristics of the coarse FF, fine FF and GP API materials used in the formulation of the co-suspension composition described in this example are detailed in Table 2. In addition to the two-drug co-suspension composition, a monotherapy co-suspension composition incorporating only the FF active agent material was formulated. This FF monotherapy co-suspension used a coarse FF API. Use such FF monotherapy co-suspension to produce monotherapy MDI and formulate this FF monotherapy MDI to deliver a delivery dose of 4.8 μg FF per actuation And manufactured.

Depending on the spray-dried emulsion: Feedstock concentration 80 mg / ml, composition 93.44% DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) and 6.56% anhydrous calcium chloride (2: 1 Suspended particles were produced with DSPC: equivalent to a CaCl ₂ mol / mole ratio. During emulsion preparation, DSPC and CaCl ₂ were dispersed at 8000-10000 rpm in a vessel containing warm water (80 ± 3 ° C.) using a high shear mixer, during which PFOB was added slowly. The emulsion was then processed in 6 passes in a high pressure homogenizer (10000-25000 psi). The emulsion was then spray dried with a specified atomizer gas flow rate of 18 SCFM using a spray dryer fitted with a 0.42 "atomizer nozzle. The drying gas flow rate was set to 72 SCFM, the inlet temperature was 135 ° C, and the outlet temperature was 70 ° C. The emulsion flow rate was 58 mL / min.

For the production of MDI, a drug addition container (DAV) for filling the suspension was prepared in the following manner. First, add half the amount of suspended particles, then fill with the microcrystalline material, and finally add the remaining half of the suspended particles on top. The substance was added to the container in a humidity controlled environment of less than 10% RH. The DAV was then connected to a 4 L suspension vessel and flushed with HFA134a propellant and mixed gently to form a slurry. The slurry is then returned to the suspension mixing vessel and diluted with additional HFA-134a to form the final suspension at the target concentration while gently stirring with an impeller. The temperature inside the container was maintained at 21-23 ° C. throughout the batch preparation. After 30 minutes of recirculation, the suspension was filled via a 50 μl valve (Bespak, Kins's Lynn, UK) into an aluminum can (Presspart, Blackburn, UK) coated with 14 mL of fluorinated ethylene polymer (FEP). Sample cans were randomly selected for comprehensive analysis of the cans to ensure the correct dosage. The optical diameter and particle size distribution of the two lots of micronized formoterol particles were measured by laser diffraction as described in Example 1. Table 2 lists the d ₁₀ , d ₅₀ and d ₉₀ values for the different lots of micronized material used. d ₁₀ , d _50, and d ₉₀ represent the particle sizes at which the cumulative volume distribution reported by the particle size measurement device reaches 10%, 50%, and 90%, respectively.

  The particle size distribution provided by both two-part co-suspension formulations prepared according to this Example 4 was compared with the particle size distribution provided by the co-suspension composition prepared according to Example 1. The results of this comparison are shown in Table 3. “FPF FF (%)” and “FPF GP (%)” in the table indicate the fine particle mass of a specific active agent on the filter from stage 3 of NGI. Divided by the mass of and multiplied by 100.

  The aerosol performance of the two-part co-suspension composition prepared according to this example was evaluated and compared with the co-suspension composition prepared according to Example 1. Aerosol performance was examined as described in Example 1. The results of such comparison are shown in FIGS. As readily understood by referring to these figures, the two-drug form, regardless of whether the crystalline formoterol material used in the two-drug co-suspension feed was fine or coarse The particle size distribution of FF and GP of the co-suspension composition was substantially the same as that achieved with the co-suspension composition prepared according to Example 1.

  In addition, the delivery dose uniformity of GP and FF provided by the two-part co-suspension composition as described in this example was examined as described in Example 1. The result of this investigation is shown in FIG. The two-drug co-suspension formulation provided the desired DDU characteristics for both GP and FF, since all working doses delivered expected doses within ± 25% of the average.

Example 5
The formulation of a two-component co-suspension composition of salmeterol xinafoate (SX) activator particles and fluticasone propionate (FP) activator particles is described. Both FP and SX are present in the propellant as finely divided crystalline particles. The two micronized active agent particles are co-suspended with the spray-dried suspension particles.

  Manufacturer of micronized SX (4-hydroxy-α1-[[[6- (4-phenylbutoxy) hexyl] amino] methyl] -1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate) 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 exhibited an optical diameter of less than 2 μm and 90% by volume exhibited an optical diameter of less than 3.9 μm.

  Micronized FP (S- (fluoromethyl) 6α, 9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate) is Received as micronized by the manufacturer (Hovione FarmaCiencia SA, Loures, Portugal) and used as activator particles. The particle size distribution of FP was measured by laser diffraction. 50% by volume of the micronized particles exhibited an optical diameter of less than 2.6 μm and 90% by volume exhibited an optical diameter of less than 6.6 μm.

  Suspended particles were produced as follows. A 150 ml phospholipid stabilized PFOB (perfluorooctyl bromide) fluorocarbon emulsion in water was prepared, 12.3 g phospholipid, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) and 1.2 g calcium chloride was homogenized in 100 ml hot water (70 ° C.) using a high shear mixer and 65 ml PFOB was added slowly during the homogenization. The resulting coarse emulsion was then further homogenized using a high pressure homogenizer (Model C3, Avestin, Ottawa, Canada) at a maximum pressure of 140 MPa over 3 passes.

  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; and total gas flow rate 498 l / min. The particle size distribution of the suspended particles, ie VMD, was measured by laser diffraction. 50% by volume of the suspended particles were less than 2.7 μm and the geometric standard deviation of the distribution was 2.0. Further, the aerodynamic particle size distribution of the suspended particles was measured using a time-flight type particle size measuring device. 50% by volume of the suspended particles had an aerodynamic particle size of less than 1.6 μm. A large difference between the aerodynamic particle size and the optical particle size indicates that the suspended particles had a low particle density of less than 0.5 kg / l. When this was verified by an electron microscope observation method, it was confirmed that the suspended particles were hollow and had a thin wall form.

  The MDI was prepared by weighing the target mass of micronized FP, SX and suspended particles into a 19 ml volume of a fluoroethylene polymer (FEP) coated aluminum can (Presspart, Blackburn, UK). This can was crimp sealed with a 63 μl valve (# BK357, Bespak, King's Lynn, UK) and 10 ml of HFA134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst) by overpressure through the valve shaft. , UK). After injection of the propellant, the cans were sonicated for 15 seconds and stirred on a wrist action shaker for 30 minutes. The can was fitted with a polypropylene actuator (# BK636, Bespak, King's Lynn, UK) with a 0.3 mm orifice. Aerosol performance was examined according to USP601 immediately after manufacture as described in Example 1. The results are reported in Table 4 below.

  When tested for delivery dose uniformity throughout use, all individual delivery doses were within ± 20% of the mean, with a relative standard deviation (also referred to as “RSD”) of 6.1%. When visual observation of the co-suspension was performed in a glass vial, no settling of active agent particles was observed. The vial was allowed to stand for 24 hours without stirring. The suspension slowly solidified to form a homogeneous single cream layer.

Example 6
The formulation of a combined co-suspension composition of salmeterol xinafoate (SX) activator particles and fluticasone propionate (FP) suspension particles is described. SX is present in the propellant as finely divided crystalline particles. This is co-suspended with spray-dried suspended particles having micronized FP placed in the material forming the suspended particles. To accomplish this, FP crystals are suspended in the feedstock used to produce lipid-based suspended particles. The FP and SX used to form the active agent particles and suspended particles referred to in this example were as described in Example 5.

  FP-containing suspended particles were produced as follows. Prepare 200 ml of a phospholipid-stabilized fluorocarbon in water emulsion of PFOB, disperse 3.3 g phospholipid (DSPC) and 0.8 g micronized FP, add 0.3 g calcium chloride dihydrate, The shear mixer was dissolved in 100 ml warm water (70 ° C.) and 44 ml PFOB was added slowly during dispersion. The resulting coarse emulsion was then further homogenized at 140 MPa for 3 passes through a high pressure homogenizer. The particle size of the suspended FP crystals was reduced by homogenization. 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 a target mass of micronized SX activator particles and FP-containing suspended particles into a volume of 19 ml fluoroethylene polymer (FEP) coated aluminum cans (Presspart, Blackburn, UK). . This can was crimp sealed with a 63 μl valve (# BK357, Bespak, King's Lynn, UK), and 10 ml of HFA134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst) by overpressure through the valve shaft. , UK). After injection of the propellant, the cans were sonicated for 15 seconds and stirred on a wrist action shaker for 30 minutes. The can was fitted with a polypropylene actuator (# BK636, Bespak, King's Lynn, UK) with a 0.3 mm orifice. Aerosol performance was examined according to USP601 immediately after manufacture as described in Example 1 above. The results are recorded in Table 5 below.

  Delivery dose uniformity throughout use was tested. All individual delivery doses were within ± 25% of the average, FP RSD was 9.0%, and SX RSD was 13%. When visual observation of the co-suspension was performed in a glass vial, no settling of active agent particles was observed. The vial was allowed to stand for 24 hours without stirring. The suspension solidified slowly, forming a homogeneous single cream layer, showing no signs of separation of SX and suspended particles.

Example 7
A formulation of a two-component co-suspension composition comprising budesonide activator particles and mometasone furoate activator particles is described. Budesonide (BD) and mometasone furoate (MF) are present in the propellant as finely divided crystalline particles and are co-suspended with the spray-dried suspended particles.

  BD, 16,17- (butylidenebis (oxy))-11,21-dihydroxy-, (11-β, 16-α) -pregna-1,4-diene-3,20-dione is the manufacturer (AARTI, Munbai, India) received and used as activator particles. The particle size distribution of BD was measured by laser diffraction. 50% by volume of the micronized particles exhibited an optical diameter of less than 1.9 μm, and 90% by volume exhibited 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 micronized by the manufacturer (AARTI, Mumbai, India) Was received and used as activator particles. The particle size distribution of MF was measured by laser diffraction. 50% by volume of the micronized particles exhibited an optical diameter of less than 1.6 μm and 90% by volume exhibited an optical diameter of less than 3.5 μm.

  Suspended particles were produced as follows. 500 ml of a phospholipid stabilized PFOB (perfluorooctyl bromide) fluorocarbon in water emulsion was prepared, 18.7 g phospholipid, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) and 1.3 g calcium chloride was homogenized in 400 ml hot water (75 ° C.) using a high shear mixer and 100 ml PFOB was added slowly during the homogenization. The resulting coarse emulsion was then further homogenized with a high pressure homogenizer (Model C3, Avestin, Ottawa, Calif.) At a pressure of up to 170 MPa for 5 passes. 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 498 l / min.

  MDI was prepared by weighing the target mass of micronized active agent and suspended particles into a coated glass vial with a volume of 15 ml. The can is crimp sealed with a 63 μl valve (Valois, Les Vaudreuil, France) and 9.2 g HFA134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst, UK) by overpressure through the valve shaft Filled. After injection of the propellant, the cans were sonicated for 15 seconds and stirred on a wrist action 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 suspended particles. The ratio of suspended particles to activator particles was 7.5 for BD and 5.5 for MF. The target dose exiting the actuator was 40 μg for BD and 55 μg for MF.

  According to visual observation of the co-suspended composition, there was no sedimentation of the activator particles. The vial was left for 16 hours without stirring. No active agent particles were visible at the bottom of the co-suspension vial. This result indicates that the crystalline budesonide and mometasone furoate materials that form different types of activator particles associated with the suspended particles formed a co-suspension of the configuration disclosed herein. It was. The association between the activator particles and the suspended particles was strong enough to overcome buoyancy to successfully inhibit the settling of the activator particles.

Example 8
A two-part co-suspension composition was prepared using suspended particles containing either mometasone furoate (MF) or budesonide (BD), and an MDI incorporating this composition was prepared. This co-suspension composition is a combination of crystalline glycopyrrolate (GP) activator particles and formoterol fumarate (FF) activator particles co-suspended with suspended particles containing either MF or BD. Was included. Each API was supplied as a finely divided crystalline material.

  Suspended particles containing 50% (w / w) of either BD or MF were produced as follows. While slowly adding 56.6 g PFOB to a dispersion containing 2.8 g DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) and 0.26 g calcium chloride in 400 ml hot water (75 ° C.) High shear homogenization was performed with a shear mixer. Micronized MF or BD (1: 1 weight ratio to DSPC) is added to the resulting coarse emulsion and this is added to a high pressure homogenizer (model C3, Avestin, Otawa, Calif.) At pressures up to 170 MPa over 3-5 passes. Was further homogenized. The emulsion was spray dried at 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 525-850 L / min. When the particle size distribution of the resulting powder was quantified by laser diffraction, 50 volume% of the suspended particles were less than 1.8 μm, and the span of the distribution was 1.6 μm.

  Cans containing either 50% (w / w) MF or BD containing suspended particles were filled with HFA134a propellant, targeting 50 μg or 100 μg MF or BD per actuation, respectively. These aerosol particle size distributions were measured by the method described in Example 1, and the results are shown in Table 6. A similar series of cans containing MF or BD containing suspended particles was made in combination with GP and FF activator particles. Fully micronized GP and FF API materials were added to the cans in amounts sufficient to provide a target delivery dose of 36 μg / actuation and 6 μg / actuation for GP and FF, respectively. Additional placebo suspension particles (also called “placebo” suspension particles) prepared as described herein but without any active agent ensure a total co-suspension concentration of 5.5 mg / ml Added to reach.

  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. The mass mean aerodynamic diameter of corticosteroids in a single component suspension is two different types of active agent particles co-suspended with suspended particles containing BD or MF. Is equivalent to the equivalent value obtained in a three-drug combination formulation prepared using As applied to the co-suspension composition containing a combination of two different active agents, the three-part co-suspension composition prepared according to the present description avoided the effect of the combination.

Example 9
A three-part co-suspension composition according to the present description was made and an MDI incorporating the composition was prepared. The composition comprises a combination of glycopyrrolate (GP) activator particles, formoterol fumarate (FF) activator particles and mometasone furoate (MF) activator particles, each micronized crystal. Supplied as a sex API substance.

  A three-part co-suspension MDI was produced by semi-automatic suspension filling. This three-part co-suspension is a combination of three microcrystalline active pharmaceutical ingredients that form three different types of active agent particles: MF (corticosteroid), GP (LAMA) and FF (LABA). Consisted of. These three different types of activator particles were co-suspended with suspended particles in HFA134a propellant. The triplicate co-suspension was formulated with the following delivery dose targets: 50 μg MF per actuation, 36 μg GP per actuation and 4.8 μg FF per actuation. In addition to this three-drug co-suspension, a monotherapy co-suspension containing only MF was prepared. This monotherapy MF co-suspension contains MF active agent particles co-suspended in a propellant with suspended particles as described in this example, which is the target delivery dose 1 Formulated to provide 50 μg MF per actuation.

Suspension particles were spray dried to a feed concentration of 80 mg / ml, 93.44% DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) and 6.56% anhydrous calcium chloride (2: 1 DSPC: equivalent to a CaCl ₂ mol / mole ratio). During emulsion preparation, DSPC and CaCl ₂ were dispersed at 8000-10000 rpm in a high shear mixer in a vessel containing warm water (80 ± 3 ° C.) and PFOB was added slowly during this process. The emulsion was then processed in 5 passes in a high pressure homogenizer (10000-25000 psi). This emulsion was then spray dried with a specified atomizer gas flow rate of 18 SCFM with a spray dryer fitted with a 0.42 "atomizer nozzle. The drying gas flow rate was set to 72 SCFM, the inlet temperature was 135 ° C, the outlet temperature was 70 ° C, The emulsion flow rate was 58 mL / min.

  For the production of MDI, a drug addition container (DAV) for filling the suspension was prepared in the following manner. First, half the amount of suspended particles is added, then filled with microcrystalline material, and finally the remaining half of the suspended particles are added on top. Substances were added to the container in a humidity controlled environment of less than 10% RH. Next, the DAV was connected to a 4 L suspension container, and the HFA134a propellant was poured, followed by mixing with a magnetic stirrer bar. The temperature inside the container was maintained at 21-23 ° C. throughout the batch preparation. After 30 minutes of batch recirculation, the suspension mixture was filled into cans via a 50 μL EPDM valve. Sample cans were randomly selected for comprehensive analysis of the cans to ensure the correct dosage. The newly prepared three-part co-suspension MDI batch was then placed in an isolation location for a week before an initial product performance analysis was performed. MDI with only mometasone furoate was prepared by suspension filling 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 aerodynamic mass mean diameter of all components during the operation of the suspension MDI were measured by drug-specific cascade impaction as described in Example 1, Is shown in Table 9.

  The aerosol performance and delivery dose uniformity achieved with the three-part co-suspension prepared according to this example was evaluated by the description shown in Example 1. FIG. 14 illustrates the GP, FF and MF DDUs achieved from two cans containing only MF and two cans containing MF, GP and FF prepared according to this example. The MF DDU delivered from the MF monotherapy composition is equivalent to the DDU achieved with the three-drug co-suspension composition. The aerosol performance of the three-part co-suspension composition prepared according to this example was also evaluated compared to a formulation containing two active agents, namely a combination of FF and GP only. The aerodynamic particle size distribution of FF and GP is equivalent as shown in FIGS. 15 and 16, respectively, regardless of whether they are delivered from a composition containing two or three active agents.

  As applicable to co-suspension compositions containing a combination of two different active agents, the three-part co-suspension composition prepared according to the present description avoided the effects of the combination.

Example 10
An exemplary three dose co-suspension composition according to this description was made and a metered dose inhaler incorporated into the composition was prepared. This three-component co-suspension contains glycopyrrolate (GP) or tiotropium bromide (TB) in combination with formoterol fumarate (FF) activator and mometasone furoate (MF) activator, Each API was used as a finely divided crystalline material.

  Two separate suspension MDI batches containing three active pharmaceutical ingredients (API), corticosteroid, LAMA and LABA were prepared. This API was provided as a microcrystalline material that functioned as active agent particles co-suspended with suspended particles prepared as described herein. A three-part co-suspension composition prepared as described in this example was prepared by adding activator particles and suspended particles to the HFA134a propellant.

The first triple dose co-suspension batch (Triple GFM) was formulated with the following delivery dose targets: 40 μg MF per actuation, 13 μg GP per actuation and 4.8 μg FF per actuation. . Using an emulsion composed of 93.46% DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) and 6.54% anhydrous calcium chloride, spray-dried with activator particles at a feed concentration of 80 mg / mL And co-suspended with the suspension particles produced. DSPC of suspended particles: CaCl ₂ molar ratio was 2: 1. The suspension particles were mixed with the active agent particles in the propellant so that the formulation target was a suspended particle concentration of 6 mg / ml. The primary particle size of microcrystalline activator particles (measured by Sympatec laser diffraction measurement as described in Example 1) is shown in Table 11 below.

  A second three-drug co-suspension batch (TFM) was prepared using a different LAMA API, anhydrous tiotropium bromide (TB) instead of GP. This second triple dose co-suspension was formulated into the following delivery dose targets: 50 μg MF per actuation, 9 μg TB per actuation, and 4.8 μg FF per actuation. Suspended particles were prepared as described for the three-drug GFM co-suspension and the active agent particles were co-suspended with the suspended particles at a target suspension concentration of 6 mg / ml. The primary particle size of microcrystalline activator particles (measured by Sympatec laser diffraction measurement as described in Example 1) is shown in Table 12 below.

  MDIs were prepared using a three-part GFM co-suspension composition and a three-part TFM co-suspension composition, and aerosol properties, fine particle fractions and median aerodynamic mass diameters are given in Example 1. Measured as described. Table 13 describes the performance of MMAD and FPF for three-part GFM and three-part TFM, and shows the desired aerosol properties achieved with the three-part GFM co-suspension and the three-part TFM co-suspension. FIG. 17 shows the aerodynamic particle size distributions of GP and TB obtained by three-drug GFM and three-drug TFM, respectively.

Example 11
An exemplary two-part co-suspension composition according to the present description was made and an MDI incorporating the two-part co-suspension composition was prepared. This composition contained a combination of glycopyrrolate (GP) and formoterol fumarate (FF), each provided as a finely divided crystalline material having a particle size distribution as shown in Table 14. . The microcrystalline GP and FF materials provided two activator particles, and the suspended particles were prepared as described in Example 4. In preparing the two-component co-suspension described in this example, GP activator particles, FF activator particles and suspended particles were mixed in an HFA134a propellant.

  The two-drug co-suspension described in this example begins with the appropriate amount of GP activator particles and FF activator particles and suspended particles added to the drug inside a humidity controlled chamber (RH less than 5%). Prepared by dispensing into containers (DAV). The DAV was then sealed under a nitrogen atmosphere and connected to a suspension vessel containing 12 kg of HFA-134a. Next, 0.5-1 kg of HFA-134a is added into the DAV to form a slurry, which is then removed from the suspension vessel and gently swirled. The slurry is then returned to the suspension mixing vessel and diluted with additional HFA-134a to form the final suspension at the target concentration while gently stirring with an impeller. The suspension is then recirculated to the filling system by a pump for a minimum amount of time before filling begins. Mixing and recirculation continues throughout the filling process. After the valve is installed on the MDI can, the air is purged either by a vacuum crimping process or by a valve crimping following the HFA-134a purge process. The crimped can is then filled with an appropriate amount of suspension through a valve and adjusted with a metering cylinder.

  The suspension for pressure filling is made by first adding an appropriate amount of micronized glycopyrrolate and formoterol fumarate crystals and suspended particles into a drug addition container (DAV) inside a humidity controlled chamber (RH less than 5%). ). In this example, the suspended particle carrier was added in three equal amounts after the first and second additions, with the addition of GP and FF, respectively. The DAV is then sealed under a nitrogen atmosphere and connected to a suspension vessel containing 12 kg of HFA-134a. Next, 0.5-1 kg of HFA-134a is added into the DAV to form a slurry, which is then removed from the suspension vessel and gently swirled. The slurry is then returned to the suspension mixing vessel and diluted with additional HFA-134a with gentle stirring with an impeller to form the final suspension at the target concentration. The suspension is then recirculated to the filling system by a pump for a minimum amount of time before filling begins. Mixing and recirculation continues throughout the filling process. After the valve is placed on the can, the air is purged either by a vacuum crimping process or by a valve crimping following the HFA-134a purge process. The crimped can is then filled with an appropriate amount of suspension through a valve and adjusted with a metering cylinder.

  MDI containing the two-drug co-suspension described in this example was prepared to contain two different doses of GP and FF. Specifically, the first batch of two-component co-suspension composition is prepared to provide 18 μg GP per actuation and 4.8 μg FF per actuation (“low dose”), A batch two-component co-suspension composition was prepared to provide 36 μg GP per actuation and 4.8 μg FF per actuation (“high dose”). In addition to this two-drug co-suspension composition, monotherapy FF and GP co-suspension compositions were prepared. The monotherapy co-suspension composition was prepared as described for the two-drug co-suspension except that it contained only one active agent particle (either GP or FF). Monotherapy co-suspensions were formulated and monotherapy MDI was formulated with the following target delivery doses: 18 μg GP per actuation and 0.5 μg, 1.0 μg, 3.6 μg or 4.8 μg FF per actuation Was prepared to provide The composition and MDI that provide 0.5 μg FF and 1 μg FF per actuation are referred to as “very low” doses.

  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. Figure shows proportionality of aerodynamic size distribution of GP obtained from low-dose and high-dose two-component co-suspensions, and equivalence between two-component co-suspensions and monotherapy co-suspensions This will be described in FIG. Similarly, the proportionality of the aerodynamic size distribution of FFs obtained from two and monotherapy co-suspensions containing ultra low dose, low dose and high dose compositions is shown in FIG. explain.

  The delivery dose uniformity of ultra-low dose FF monotherapy MDI was also measured as described in Example 1. The DDU for the 1 μg / actuation and 0.5 μg / actuation compositions and systems is shown in FIG. The desired dose delivery uniformity is achieved even with very low doses.

Example 12
The safety, efficacy and PK performance of the combination co-suspension compositions described herein delivered by metered dose inhaler (MDI) were evaluated in clinical trials. The combined co-suspension composition contained both glycopyrrolate and formoterol fumarate. Clinical trials were randomized, double-blind, customized, non-equilibrium conducted in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) ( It was an unbalanced), multi-center study of incomplete blocks and crossover. Comparison of two different combination co-suspension compositions described herein with placebo and four comparator compositions delivering only one of the two active agents contained in the combination composition did.

The two combined co-suspension compositions administered in this clinical trial contained both glycoprolate (GP) and formoterol fumarate (FF) active agent administered as a fixed combination. Combination co-suspensions are generally prepared as described in Example 4, GP and FF activator particles are provided as micronized, crystalline GP and FF materials, and suspended particles are DSPC and CaCl _2. The suspension medium is formed by HFA134a. The combined co-suspension composition was prepared for administration to patients by MDI as described herein and was adjusted to facilitate administration of two different doses of GP and FF active agents. The first co-suspension combination composition is formulated to deliver 36 μg GP and 4.8 μg FF to the patient per MDI actuation, and 72 μg GP and 9.6 μg FF to the patient twice a day. The dose was used in patients (2 working doses of MDI were administered twice daily). This first composition and treatment is referred to as "GP / FF 72 / 9.6" and "GP / FF 72 / 9.6 treatment" in this example and in the following figures. The second co-suspension combination composition is formulated to deliver 18 μg GP and 4.8 μg FF to the patient per actuation of MDI, and the patient receives 36 μg GP and 9.6 μg FF twice per day for the patient (Two workings of MDI were administered twice a day). This second composition and treatment is referred to as "GP / FF 36 / 9.6" and "GP / FF 36 / 9.6 treatment" in this example and in the following figures.

GP / FF 72 / 9.6 treatment and GP / FF 36 / 9.6 treatment were compared against five different active compositions and placebo containing one of FF, GP or tiotropium as a single active agent. The first composition was an active control, Spiriva Handihaler (tiotropium bromide inhaled powder). Spiriva is a dry powder inhaler (DPI) product that was administered to patients once a day and each DPI capsule contained an 18 μg dose of tiotropium. The following composition, Foradil Aerolizer (formoterol fumarate inhaled powder) was also an active control. Foradil is also a DPI product, which was administered to patients twice a day and contained 12 μg doses of FF for each DPI capsule. The third composition was a co-suspension composition containing only GP as the active agent. A monotherapy GP co-suspension composition (GP 36) was manufactured for pulmonary delivery by MDI and was administered twice per day, with each administration delivering a 36 μg dose of GP to the patient. The remaining two compositions were two different monotherapy co-suspension compositions containing only FF (FF 9.6 and FF 7.2) as active ingredients. Monotherapy FF co-suspension compositions are manufactured for pulmonary delivery by MDI and are administered twice daily, each dose comprising a 9.6 μg dose of FF (FF 9.6) or a 7.2 μg dose of FF ( FF 7.2) was delivered to the patient. The GP and FF monotherapy co-suspension composition comprises a micronized, crystalline GP or FF material as active agent particles, spray-dried particles containing DSPC and CaCl ₂ as suspension particles, and a suspension medium. Formulated using HFA134a.

118 patients were randomized in this study and administered the composition over a 7 day period. In the treatment day 7, over each period of time after administration 12 hours of the composition an improvement in FEV ₁ was evaluated in each patient, the improvement of FEV ₁ versus baseline provided by each composition for a period of 12 hours The area under the curve (AUC _0-12 ) was calculated. AUC _0-12 with treatment on day 7 (day 7) was used as the primary endpoint of the study (primary endpoint). Secondary endpoints (Secondary endpoints: secondary- endpoint), each peak change in FEV ₁ after administration of the composition at day 1 and day 7 (the peak FEV _1), after long-term administration of 7 days However, it included the trough FEV ₁ (Morning trough FEV ₁ ) experienced by patients prior to administration on the seventh day of treatment and safety assessment. The two GP / FF co-suspension compositions were safe and well tolerated.

The percentage of patients with > 12% FEV ₁ improvement from baseline on treatment day 1 (Day ₁ ) and the rate at which such improvement was obtained are shown in FIG. As can be seen from FIG. 21, the cumulative response and rate of expression provided by GP / FF 72 / 9.6 and GP / FF 36 / 9.6 treatments is greater than the cumulative response and rate of onset provided by Spiriva. It was big. For comparative compositions containing only a single active agent, GP / FF 72 / 9.6 and GP / FF 36 / 9.6 treatment provided a greater change from baseline at day 7 FEV ₁ (Figure 22 to FIG. 24).

GP / FF 72 / 9.6 and GP / FF 36 / 9.6 outperformed all comparators with respect to the primary endpoint. FIG. 25 shows the improvement of FEV ₁ AUC _0-12 provided by each of GP / FF 72 / 9.6, GP / FF 36 / 9.6 and the activity comparator for placebo placebo. As can be seen from FIG. 25, GP / FF 72 / 9.6 and GP / FF 36 / 9.6 provide a very good improvement with FEV ₁ AUC _0-12 on day 7 for the comparator composition. The improvement of FEV ₁ AUC _0-12 on Day 7 provided by GP / FF 72 / 9.6 and GP / FF 36 / 9.6 was at least 80 ml more than that provided by each of the comparator compositions. The difference in Day 7 FEV ₁ AUC _0-12 shown in FIG. 26 is the 7th day provided by GP / FF 36 / 9.6 composition for GP 36, FF 9.6, Spiriva, and Foradil comparators. Further emphasize the improvement of FEV ₁ AUC _0-12 .

Using the improvement in FEV ₁ AUC _0-12 provided by GP / FF 72 / 9.6 treatment as a reference point, FIG. 32 shows that all patients, patients with moderate COPD, and severe to very FIG. 5 shows the percent improvement in FEV ₁ AUC _0-12 at day 7 provided by GP / FF 36 / 9.6 and each of the comparators in patients with severe COPD. The results shown in FIG. 32 indicate that the patient response 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 comparators with respect to the secondary endpoint of this study. Peak FEV ₁ shown in FIG. 27 represents the change in baseline provided by each active agent composition for placebo on Day 1 and Day 7 of administration. As shown in FIG. 27, GP / FF 72 / 9.6 and GP / FF 36 / 9.6 provided excellent peak FEV ₁ on both day 1 and day 7. FIG. 28 highlights the improvement in peak FEV ₁ for Spiriva and Foradil provided by GP / FF 72 / 9.6 and GP / FF 36 / 9.6 at 1 and 7 days. FIG. 29 shows the improvement in Morning Trough FEV ₁ provided by GP / FF 72 / 9.6, GP / FF 36 / 9.6, and active comparator, respectively, versus placebo. As can be seen with reference to FIG. 29, the excellent increase in FEV ₁ provided by the two combined co-suspensions is well retained for a long time, with GP / FF 72 / 9.6 and GP / FF 36 / 9.6 compositions. Offers about 50% improvement with Morning Trough FEV ₁ over other active comparators.

FIG. 30 shows the increase in pre-dose FEV ₁ on day 7 provided by GP / FF 72 / 9.6 and GP / FF 36 / 9.6, and GP 36, FF 9.6, Spiriva and Foradil comparators. The difference from the increase in pre-dose FEV ₁ on day 7 provided is shown. As can be easily understood with reference to FIG. 30, for GP 36, FF 9.6, Spiriva and Foradil comparators, GP / FF 36 / 9.6 treatment was significantly higher improvement at pre-dose FEV ₁ on day 7. Provided.

  In addition to specific secondary endpoints, this study evaluated improvements in inspiratory capacity (IC). Both GP / FF 72 / 9.6 and GP / FF 36 / 9.6 increased significantly in the IC for each of the comparators on day 1 and day 7. For patients receiving GP / FF 72 / 9.6, GP / FF 36 / 9.6, and Spiriva, FIG. 31 shows peak improvement in IC experienced on day 1 (day 1, peak), Improvement in IC retained in patients prior to administration of specific test composition on day 7 (day 7, pre), and in IC experienced in patients on day 7 after administration of specific composition Peak improvement (day 7, peak) is shown.

Claims (61)

A method of treating a lung disease or disorder in a patient comprising:
Providing a pharmaceutically acceptable co-suspension, wherein the co-suspension is
A suspending medium comprising a pharmaceutically acceptable propellant;
Two or more active agents;
One or more respirable active agent particles; and one or more respirable suspension particles, wherein the active agent particles and the suspended particles associate and co-suspend in a suspension medium. Forming a fluid; and administering the co-suspension to a patient as a breathable aerosol, wherein the co-suspension administration comprises administering to the patient a therapeutically effective amount of the two or more active agents. Delivering to the method. Providing a pharmaceutically acceptable co-suspension, short-acting beta agonists, long-acting and ultra-long-acting beta _2-adrenergic receptor agonists _{(long-acting β 2 adrenergic receptor} agonist : LABA), corticosteroids, anti-inflammatory drugs, antitussives, bronchodilators, muscarinic antagonists and long-acting muscarinic antagonists (LAMA) active agents, where any of them 2. The method of claim 1 comprising providing a co-suspension comprising two or more active agents selected from comprising a pharmaceutically acceptable salt, ester, isomer or solvate. The lung disease or disorder is asthma, COPD, chronic bronchitis, emphysema, bronchiectasis, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergy, impeded respiration, respiratory distress syndrome, lung 3. The method of claim 2, wherein the method is selected from at least one of hypertension, pulmonary vasoconstriction, pulmonary inflammation associated with cystic fibrosis, and pulmonary obstruction associated with cystic fibrosis. Providing a pharmaceutically acceptable co-suspension includes providing a co-suspension, wherein at least one of the suspended particles comprises an active agent, the two These activators are LAMA activators selected from glycopyrrolate, dexpyronium, tiotropium, trospium, acridinium, and darotropium, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin-or indole- containing and adamantyl - LABA active agent selected from the derived beta ₂ agonists, as well as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl - prednisolone, corticosteroids active selected mometasone, prednisone and Torimashinoron 4. A method according to claim 3, wherein the method is selected from including sexual agents, wherein pharmaceutically acceptable salts, esters, isomers or solvates thereof. Providing a pharmaceutically acceptable co-suspension includes providing a co-suspension comprising at least two different active agent particles, each of the at least two active agent particles being a different active agent. Wherein the different active agents are LAMA active agents selected from glycopyrrolate, dexpyronium, tiotropium, trospium, acridinium, and darotropium, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin or LABA activators selected from -indole-containing and adamantyl-derived β ₂ agonists and from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone 4. The method according to claim 3, wherein the method is selected from selected corticosteroid active agents, wherein these include pharmaceutically acceptable salts, esters, isomers or solvates thereof. Providing a pharmaceutically acceptable co-suspension includes providing a co-suspension comprising at least three different active agent particles, each of the at least three different active agent particles having different activities. And the different active agents are LAMA active agents selected from glycopyrrolate, dexpyronium, tiotropium, trospium, acridinium, and darotropium, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin LABA activators selected from -or indole-containing and adamantyl-derived β ₂ agonists, and beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolol 6. The method of claim 5, wherein the corticosteroid active agent selected from the group comprising a pharmaceutically acceptable salt, ester, isomer or solvate thereof. Providing a pharmaceutically acceptable co-suspension comprises providing a co-suspension comprising at least two different active agent particles, each of the at least two active agents being a different active agent. Wherein at least one of the at least one suspended particle comprises a third active agent, wherein the different active agent is selected from glycopyrrolate, dexpyronium, tiotropium, trospium, acridinium, and darotropium LABA active agents selected from activators, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-inducible β ₂ agonists, and beclomethasone, budesonide, ciclesonide, Flunisolide, fluticasone, 4. A corticosteroid activator selected from til-prednisolone, mometasone, prednisone and trimacinolone, wherein it comprises a pharmaceutically acceptable salt, ester, isomer or solvate thereof. The method described in 1. Delivering a therapeutically effective amount of two or more active agents to a patient includes LAMA active agents selected from glycopyrrolate, dexpyronium, tiotropium, trospium, acridinium, and darotropium, and bambuterol, clenbuterol, formoterol, salmeterol, LABA activators selected from carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β ₂ agonists, where their pharmaceutically acceptable salts, esters, isomers or solvates 4. The method of claim 3, comprising simultaneously delivering a therapeutically effective amount of the substance. Delivering a therapeutically effective amount of two or more active agents to a patient includes LAMA active agents selected from glycopyrrolate, dexpyronium, tiotropium, trospium, acridinium, and darotropium, and beclomethasone, budesonide, ciclesonide, flunisolide, A therapeutically effective amount of a corticosteroid activator selected from fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, including pharmaceutically acceptable salts, esters, isomers or solvates thereof. 4. The method of claim 3, comprising delivering simultaneously. Delivering a therapeutically effective amount of two or more active agents to a patient includes bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β ₂ agonists And a corticosteroid active agent selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone, wherein pharmaceutically acceptable salts thereof, 4. The method of claim 3, comprising delivering simultaneously a therapeutically effective amount of an ester, isomer or solvate. Delivering a therapeutically effective amount of two or more active agents to a patient includes LAMA active agents selected from glycopyrrolate, dexpyronium, tiotropium, trospium, acridinium, and darotropium, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol LALAB activators selected from milbeterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived β ₂ agonists, and beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisone and trimacinolone Simultaneously deliver a therapeutically effective amount of a corticosteroid active agent selected from, including pharmaceutically acceptable salts, esters, isomers or solvates thereof The method of claim 3 comprising: The administration of the co-suspension to a patient, results in a clinically significant increase in FEV ₁ of patients, method of any of claims 1 to 11. 13. The method of claim 12, wherein administering the co-suspension to a patient results in an increase in FEV ₁ of at least 150 mL within a time selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less. 14. The method of claim 13, wherein administering the co-suspension to a patient results in an increase in FEV ₁ of at least 200 mL within a time selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less. 15. The method of claim 14, wherein administering the co-suspension to a patient results in an increase in FEV ₁ of at least 250 mL within a time selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less. The administration of the co-suspension to the patient, 0.5 hours or less, 1 hour or less, and provide at least 300mL increase in FEV ₁ in the 1.5-hour time selected from the following, the method according to claim 15. 17. The method of claim 16, wherein administering the co-suspension to a patient results in an increase in FEV ₁ of at least 350 mL within a time selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less. The clinically significant increase in FEV ₁ achieved by administering the co-suspension to the patient is selected from up to 4 hours, up to 6 hours, up to 8 hours, up to 10 hours, and up to 12 hours or more. The method according to claim 1, which remains clinically significant within a certain time. When the co-suspension is administered to a patient, an increase of 10% or more in FEV ₁ in a time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours or less in 50% or more of patients 18. The method of any of claims 1-17, wherein When the co-suspension is administered to patients, an increase of 10% or more in FEV ₁ in a time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours or less in 60% or more of patients 18. The method of any of claims 1-17, wherein When the co-suspension is administered to patients, an increase of 10% or more in FEV ₁ in a time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours or less in 70% or more of patients 18. The method of any of claims 1-17, wherein When the co-suspension is administered to a patient, an increase of 10% or more in FEV ₁ in a time selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours or less in 80% or more of patients 18. The method of any of claims 1-17, wherein When the patient is administered the co-suspension, either an increase of at least 200 ml from the baseline of FEV ₁ , or a total increase of at least 150 mL of FEV ₁ , plus an increase of 12% or more from the baseline of FEV ₁ 12. A method according to any preceding claim, wherein the patient will experience. When the co-suspension is administered to the patient, at least 150 mL of FEV within a time selected from an FEV ₁ baseline increase of at least 200 ml, or 1 hour or less, 1.5 hours or less, 2 hours or less, and 2.5 hours or less. comprising either 12% or more increase from the total increase amount in addition to FEV ₁ of baseline in ₁ to a patient experiencing method according to any of claims 1 to 11. An increase of at least 200 mL from the FEV ₁ baseline, or a total increase of at least 150 mL of FEV ₁ plus 12% or more from the FEV ₁ baseline of 1 hour or less, 1.5 hours or less, 2 hours or less, and 25. The method of claim 24, experienced in at least 50% of patients within a time selected from 2.5 hours or less. An increase of at least 200 mL from the FEV ₁ baseline, or a total increase of at least 150 mL of FEV ₁ plus 12% or more from the FEV ₁ baseline of 1 hour or less, 1.5 hours or less, 2 hours or less, and 26. The method of claim 25, wherein the method is experienced by at least 60% of patients within a time selected from 2.5 hours or less. An increase of at least 200 mL from the FEV ₁ baseline, or a total increase of at least 150 mL of FEV ₁ plus 12% or more from the FEV ₁ baseline of 1 hour or less, 1.5 hours or less, 2 hours or less, and 25. The method of claim 24, experienced by at least 70% of patients within a time selected from 2.5 hours or less. An increase of at least 200 mL from the FEV ₁ baseline, or a total increase of at least 150 mL of FEV ₁ plus 12% or more from the FEV ₁ baseline of 1 hour or less, 1.5 hours or less, 2 hours or less, and 25. The method of claim 24, experienced in at least 80% of patients within a time selected from 2.5 hours or less. Administering the co-suspension to a patient results in a clinically significant increase in FEV ₁ in the patient, and a clinically significant increase in FEV ₁ is only one of the two or more active agents. 29. The method of any one of claims 1-28, wherein the method is a significant improvement over the increase provided by the composition that delivers. 30. The method of claim 29, wherein the significant improvement in FEV ₁ is 70 ml or greater. 32. The method of claim 30, wherein the significant improvement in FEV ₁ is 80 ml or greater. 32. The method of claim 31, wherein the significant improvement in FEV ₁ is 90 ml or greater. The significant improvement is measured as an improvement in peak FEV _1, A method according to any one of claims 30 to 32. The significant improvement is measured as an improvement in FEV ₁ AUC _0-12, a method according to any one of claims 30 to 32. 35. The method of any of claims 1-34, wherein administering the co-suspension to a patient results in a clinically significant increase in deep expiratory volume (IC). 36. The method of claim 35, wherein the clinically significant increase in IC is an increase of 100 ml or more. 37. The method of claim 36, wherein the clinically significant increase in IC is an increase of 200 ml or more. 38. The method of claim 37, wherein the clinically significant increase in IC is an increase of 300 ml or more. 40. The method of claim 38, wherein the clinically significant increase in IC is an increase of 350 ml or more. 40. The method of any of claims 35-39, wherein a clinically significant increase in IC is achieved within 2 hours. 41. The method of any of claims 35-40, wherein a clinically significant increase in IC is achieved within 1 hour. The co-suspension medium included in the co-suspension provided and administered as a respirable aerosol comprises a propellant selected from HFA propellants, PFC propellants and combinations thereof, wherein the propellant is 42. A method according to any of claims 1-41, substantially free of additional components. The co-suspension medium contained in a co-suspension provided and administered as a respirable aerosol consists essentially of a propellant selected from HFA propellants, PFC propellants and combinations thereof, 43. A method according to any of claims 1-42, wherein the propellant is substantially free of additional components. The two or more active agents included in the co-suspension provided and administered as a respirable aerosol are LAMA active agents selected from glycopyrrolate, dexpyronium, tiotropium, trospium, acridinium, and darotropium, wherein Including pharmaceutically acceptable salts, esters, isomers or solvates thereof as well as bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol, and saligenin- or indole-containing and adamantyl-derived LABA active agents selected from β ₂ agonists, here including their pharmaceutically acceptable salts, esters, isomers or solvates, provided and administered as a respirable aerosol Suspension suitable for breathing contained in co-suspension The particles are at least one of lipids, phospholipids, nonionic detergents, polymers, nonionic block copolymers, surfactants, nonionic surfactants, biocompatible fluorinated surfactants, carbohydrates and combinations thereof 44. A method according to any of claims 1-43, comprising an excipient selected from one. 45. The method of claim 44, wherein the respirable suspended particles comprise a porous microstructure. 46. A method according to any of claims 44 and 45, wherein the respirable suspended particles comprise DSPC and calcium chloride. 47. At least 50% by volume of the active agent particles contained in a co-suspension provided and administered as a respirable aerosol exhibits an optical diameter of 5 μm or less. The method described. Respirable suspended particles contained in a co-suspension provided and administered as a respirable aerosol are about 1 mg / ml to about 15 mg / ml, about 3 mg / ml to about 10 mg / ml, about 48. The method of any of claims 1-47, wherein the method is included in the suspending medium at a concentration selected from 5 mg / ml to about 8 mg / ml, and about 6 mg / ml. The respirable suspended particles contained in the co-suspension provided and administered as a respirable aerosol are selected from about 10 μm to about 500 nm, about 5 μm to about 750 nm, about 1 μm to about 3 μm. 49. A method according to any one of claims 1 to 48, which exhibits MMAD. The respirable suspended particles contained in the co-suspension provided and administered as a respirable aerosol are about 0.2 μm to about 50 μm, about 0.5 μm to about 15 μm, about 1.5 μm to about 10 μm, 50. The method of any of claims 1-49, wherein the method exhibits a volume median optical diameter selected from about 2 [mu] m to about 5 [mu] m. The ratio of the total mass of suspended particles suitable for respiration to the total mass of at least one drug particle is greater than about 1.5, up to about 5, up to about 10, up to about 15, up to about 17, up to about 20, 51. The method of any of claims 1-50, wherein the method is selected from up to about 30, up to about 40, up to about 50, up to about 60, up to about 75, up to about 100, up to about 150, and up to about 200. The ratio of the total mass of at least one suspended particle to the total mass of at least one active agent particle is selected from about 3: 1 to about 15: 1 and about 2: 1 to about 8: 1. Item 52. The method according to any one of Items 1 to 51. The respirable suspended particles contained in the co-suspension provided and administered as a respirable aerosol are centrifuged at an acceleration selected from at least 1 g, at least 10 g, at least 50 g, and at least 100 g acceleration. 53. A method according to any of claims 1 to 52, which remains associated with the active agent particles even when exposed to buoyancy amplified by separation. The active agent particles contained in the co-suspension provided and administered as a respirable aerosol comprise first and second type active agent particles, said first type of activated particles being glycopyro A second active agent particle comprising formoterol, a pharmaceutically acceptable salt, ester, isomer or solvate thereof. 54. The method according to any one of claims 1 to 53, comprising a product. 55. The method of claim 54, wherein the first type of activator particles comprises crystalline glycopyrrolate and the second type of activator particles comprises crystalline formoterol. The co-suspension provided and administered as an aerosol suitable for respiration is an HFA propellant substantially free of additional components, two activities provided as first and second active agent particles. And respirable suspended particles formed from a phospholipid excipient, wherein the two active agents are provided as first and second active agent particles. Wherein the first type of active agent particles comprises crystalline glycopyrrolate, pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the second type of active agent particles comprises formoterol, 55. The method of claim 54, comprising a pharmaceutically acceptable salt, ester, isomer or solvate. 57. The method of any of claims 1-56, wherein the pharmaceutically acceptable co-suspension is provided in and administered from MDI. Administering a co-suspension to a patient as an aerosol suitable for breathing includes administering the co-suspension to the patient up to twice per day, each administration comprising only 150 μg of LAMA active agent and LABA active agent 58. The method of any of claims 44-57, comprising delivering 12 [mu] g. Administering the co-suspension to the patient as an aerosol suitable for breathing involves administering the co-suspension to the patient up to 2 times per day, each dose comprising only 100 μg of LAMA active agent and LABA active agent 59. The method according to any of claims 44-58, comprising delivering 12 [mu] g. Administering the co-suspension to the patient as an aerosol suitable for breathing involves administering the co-suspension to the patient up to twice per day, each administration comprising only 80 μg of LAMA active agent and LABA active agent 60. The method of any of claims 44-59, comprising administering 12 [mu] g. Administering the co-suspension to the patient as a respirable aerosol includes administering the co-suspension to the patient up to 2 times per day, each administration containing only 50 μg of LAMA active agent and LABA active agent 61. The method according to any of claims 44-60, comprising administering 12 [mu] g.

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