RU2574893C2 - COMPOSITIONS FOR PULMONARY DELIVERY OF LONG-ACTING MUSCARINIC ANTAGONISTS AND LONG-ACTING β2-ADRENERGIC RECEPTOR AGONISTS AND RELATED METHODS AND SYSTEMS - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a group of 13 inventions. It includes compositions and methods for respiratory delivery of formoterol, a long-lasting muscarinic antagonist and/or glycopyrrolate, a long-lasting β₂-adrenergic receptor agonist through an inhaler with a metered dose, as well as the above inhaler and methods of treating a pulmonary disease or disorder with using them. The pharmaceutical composition and the inhaler containing it contain the above active substances, a number of suspending particles insoluble in a suspension medium, dry perforated microstructures containing phospholipid; total weight of the suspending particles exceeds that of the active substance and forms a co-suspension with them.

EFFECT: technical effect consists in providing the physical and chemical stability of the composition, providing uniformity of the dose delivered by the co-suspension as far as the inhaler clears.

140 cl, 30 dwg, 14 tbl

Description

Technical area

The present invention relates mainly to pharmaceutical compositions and methods for delivering one or more active substances through the respiratory tract. In certain aspects, the present invention relates to compositions, methods and systems for pulmonary delivery of long acting muscarinic receptor antagonists and long acting β ₂ adrenergic receptor agonists via a metered dose inhaler.

State of the art

Often, targeted drug delivery methods that deliver the active substance to the field of action are desirable. For example, targeted delivery of active substances can reduce unwanted side effects, reduce the required dosage and reduce the cost of treatment. In the context of respiratory delivery, inhalers are well-known devices for administering an active substance to the respiratory tract of an individual, and several different inhalation systems are currently available. Three well-known inhalation systems include dry powder inhalers, nebulizers and metered dose inhalers (MDI).

MDI can be used for drug delivery in solubilized form or as a suspension. Typically, MDI uses a relatively high vapor pressure propellant to expel aerosolized droplets containing the active substance into the airways when the MDI is activated. Dry powder inhalers are typically based on the patient's respiratory efforts to inject the drug powder into the airways in the form of a dry powder. On the other hand, nebulizers form an aerosol of the drug to be inhaled by transferring energy to a liquid solution or suspension.

MDIs are active substance delivery devices that use propellant pressure. Typically, chlorofluorocarbons (CFCs) are used as propellants in MDI systems because of their low toxicity, the desired vapor pressure and their suitability for the formation of stable suspensions. However, it is understood that traditional CFC propellants have a negative environmental impact, which has led to the development of alternative propellants that are believed to be more environmentally friendly, such as perfluorinated compounds (PFCs) and hydrofluoroalkanes (HFAs).

The active substance to be delivered by suspension in MDI is typically provided as fine particles dispersed in a propellant or a combination of two or more propellants (ie, in a propellant “system”). For the formation of fine particles, the active substance is typically micronized. Fine particles of the active substance suspended in a propellant or propellant system tend to rapidly aggregate or settle in the form of flakes. This is especially true for active substances present in micronized form. In turn, aggregation or sedimentation in the form of flakes of these fine particles can complicate the delivery of the active substance. For example, aggregation or settling in the form of flakes can lead to mechanical damage, such as damage that can be caused by blockage of the valve opening of the aerosol container. Unwanted aggregation or sedimentation in the form of flakes of drug particles can also lead to rapid sedimentation or exfoliation of drug particles, and this behavior can lead to unstable dose delivery, which, in turn, can cause particular difficulties in the case of highly potent low-dose drugs . Another problem associated with such suspension formulations for MDI relates to the growth of drug crystals during storage, which leads to a decrease in aerosol properties over time and uniformity of the delivered dose from such MDIs. Approaches to solve these problems were later proposed, such as those described in US Pat. 6964759, for MDI formulations containing anticholinergics.

One approach to improve aerosol performance in dry powder inhalers is to incorporate particulate carriers such as lactose. The use of such finely divided excipients has not been studied to a large extent for MDI. In a recent report by Young et al., "The influence of micronized particulates on the aerosolization properties of pressurized metered dose inhalers"; Aerosol Science 40, pgs. 324-337 (2009), it is indicated that the use of such carriers of fine particles in MDI actually leads to a deterioration in aerosol performance.

In traditional CFC systems, when the active agent present in the MDI is solubilized in the propellant or propellant system, surfactants are often used to coat the surfaces of the active agent in order to minimize or prevent the problem of aggregation and maintain a substantially uniform dispersion. The use of surfactants is thus sometimes called "stabilization" of the suspension. However, many surfactants that are soluble and thus effective in CFC systems are not effective in HFA and PFC propellant systems, since such surfactants exhibit different solubility characteristics in non-CFC propellants.

Brief Description of Drawings

In FIG. 1 is a graph depicting the particle size distribution exemplified by the illustrative slurry composition as described herein, which included a glycopyrrolate, a long acting muscarinic receptor antagonist, as an active substance. Co-suspension MDI was subjected to temperature cycling (alternating holding for 6 hours at -5 or 40 ° C) for 12 weeks.

In FIG. 2 is a graph depicting the particle size distribution exhibited by the illustrative slurry composition as described herein, which included a glycopyrrolate, a long acting muscarinic receptor antagonist, as an active substance. Co-suspension MDI was subjected to temperature cycling (alternating holding for 6 hours at -5 or 40 ° C) for 24 weeks.

In FIG. 3 is a photomicrograph illustrating the morphology of various suspending particles obtained according to example 5.

In FIG. 4 is a photograph of two vials that allows visualization of the co-suspension formed using active substance particles formed using glycopyrrolate and suspending particles formed using saccharide.

In FIG. 5 is a graph depicting a serum glycopyrrolate concentration level achieved within 24 hours after a single administration of four different doses of glycopyrrolate delivered using a co-suspension composition as described herein.

In FIG. 6 is a graph showing the average change in FEV ₁ from the baseline (in liters) experienced by patients over a period of 24 hours after a single dose of a specified dose of glycopyrrolate formulated in cosuspension as described herein. In this study, Spiriva (18 μg tiotropium) was included as an active control, and the average change in FEV ₁ from baseline (in liters) experienced by patients who had a single dose of Spiriva was also presented.

In FIG. 7 is a bar graph showing the change in peak of FEV ₁ from the baseline (in liters) experienced by patients after a single dose of a specified dose of glycopyrrolate made in a suspension, as described herein, relative to placebo, the area under the FEV curve ₁ within 12 hours after dosing, and the area under the FEV curve ₁ for 24 hours after dosing relative to placebo for the four doses evaluated. In this study, Spiriva (18 μg tiotropium) was included as an active control, and the results after a single administration of Spiriva for the above parameters are also presented in this figure.

In FIG. 8 is a graph showing the proportion of patients who achieved more than 12% change in FEV ₁ from the baseline and an improvement in the form of a change of 150 ml from the baseline or an absolute improvement in the form of 200 ml from the baseline, regardless of the% change in FEV ₁ from the initial level, after a single injection of the indicated doses of the suspension of glycopyrrolate, as described herein. In this study, Spiriva (18 μg tiotropium) was included as an active control, and the results after a single administration of Spiriva for the above parameters are also presented in this figure.

In FIG. 9 is a bar graph that shows the change in peak inspiratory capacity in patients after a single dose of the indicated doses of glycopyrrolate cosuspension, as described herein. In this study, Spiriva (18 μg tiotropium) was included as an active control, and the results after a single administration of Spiriva for the above parameters are also presented in this figure.

In FIG. 10 is a bar graph showing the change in AUC for FEV ₁ achieved in patients after a single administration of the indicated doses of glycopyrrolate cosuspension as described herein. The results achieved by the co-suspension of glycopyrrolate as described herein are presented compared to the change in AUC FEV ₁ described in a published study in patients who were injected with a powder composition of glycopyrrolate that was not prepared as directed in this document.

In FIG. 11 is a graph depicting the particle size distribution of an exemplary glycopyrrolate cosuspension obtained according to the present description, containing 4.5 μg of glycopyrrolate per dose delivered at actuation and 6 mg / ml of suspending particles and subjected to temperature cycling (holding for 6 hours at -5 or 40 ° C).

In FIG. 12 is a graph depicting the particle size distribution of an exemplary glycopyrrolate cosuspension obtained according to the present description, containing 36 μg of glycopyrrolate / delivered upon activation of a dose and 6 mg / ml of suspending particles and subjected to temperature cycling (alternating holding for 6 hours at -5 or 40 ° C).

In FIG. 13 is a graph showing the delivered dose over the course of being in the container of an illustrative glycopyrrolate cosuspension, prepared as described herein, containing 4.5 μg of glycopyrrolate / delivered when the dose was activated and 6 mg / ml of suspending particles.

In FIG. 14 is a graph showing the delivered dose over the course of being in the container of the illustrative glycopyrrolate cosuspension obtained according to the present description, containing 36 μg of glycopyrrolate / delivered upon activation, the dose and 6 mg / ml of suspending particles.

In FIG. 15 is a graph showing the particle size distribution of an illustrative glycopyrrolate cosuspension, prepared according to the present description, containing 36 μg of glycopyrrolate / delivered upon activation, the dose and 6 mg / ml of the suspending particles and stored for 12 months at 25 ° C / 60 % RH in the absence of protection.

In FIG. 16 is a graph that depicts the average delivered dose over the duration of an illustrative glycopyrrolate cosuspension obtained in accordance with the present description containing 32 μg of glycopyrrolate / delivered upon activation of a dose and 6 mg / ml of suspending particles and subjected to temperature cycling (alternating aging) for 6 hours at -5 or 40 ° C).

In FIG. 17 is a graph showing the particle size distribution of an exemplary glycopyrrolate cosuspension obtained according to the present description, containing 32 μg of glycopyrrolate / delivered upon activation, the dose and 6 mg / ml of the suspending particles and subjected to a cyclic temperature change (alternating holding for 6 hours at -5 or 40 ° C).

In FIG. 18 is a graph depicting a particle size distribution of an exemplary glycopyrrolate cosuspension obtained according to the present description, containing 24 μg of glycopyrrolate / delivered upon activation, dose and 6 mg / ml of suspending particles and stored for 6 weeks at 50 ° C / atmospheric relative humidity and for 12 weeks at 40 ° C.

In FIG. 19 is a photograph that allows visualization of the cosuspension compositions prepared according to the present description, which include particles of the active substance formoterol fumarate.

In FIG. 20 is a graph showing the uniformity of the delivered dose achieved using the cosuspension formoterol fumarate compositions prepared according to the present description.

In FIG. 21 is a graph showing the aerodynamic particle size distribution determined using a cascade impactor of illustrative co-suspension formoterol fumarate compositions prepared as described herein and stored for three months at 25 ° C / 75% RH with a protective wrap or at 40 ° C / 75% RH without protective wrap.

In FIG. 22 is a graph depicting the chemical stability of exemplary antisuspension compositions comprising formoterol fumarate as an active substance. The results presented in this figure allow a comparison of the chemical stability of formoterol fumarate achieved in a co-suspension composition made using crystalline formoterol fumarate with the chemical stability of suspension compositions obtained using spray-dried formoterol fumarate.

In FIG. 23 - FIG. 26 is an electron micrograph of suspending particles obtained from various materials, wherein FIG. 23 is a micrograph of suspending particles of trehalose, FIG. 24 is a micrograph of suspending particles of HP-β-cyclodextrin, FIG. 25 is a micrograph of suspending particles of Ficoll MP70, and FIG. 26 is a view. micrograph of suspending particles of inulin.

In FIG. 27 is a graph showing the aerodynamic particle size distribution determined by sequentially compressing illustrative slurry compositions prepared as described herein and including particles of the active substance glycopyrrolate.

In FIG. 28 is a graph showing the aerodynamic particle size distribution determined by sequentially compressing illustrative slurry compositions prepared as described herein and including particles of the active substance formoterol fumarate.

In FIG. 29 is a graph depicting the uniformity of the delivered dose achieved using ultra-low dose formoterol fumarate formulations, prepared in accordance with the present description.

In FIG. 30 is a graph illustrating the particle size distribution of glycopyrrolate (top) and formoterol (bottom) achieved by illustrative co-suspension compared to particle size distributions achieved by formulations comprising either glycopyrrolate or formoterol fumarate alone.

Detailed description

The present invention relates to compositions, methods and systems for respiratory delivery of active substances using MDI. In specific embodiments, the compositions, methods and systems described herein are adapted for respiratory delivery of active substances selected from a long acting muscarinic receptor antagonist ("LAMA") and a long acting β ₂ -adrenergic receptor agonist ("LABA"). In certain embodiments, the active substance LAMA or LABA can be potent or potent and, thus, manufactured in low concentrations and delivered in low doses. The pharmaceutical compositions described herein can be formulated for pulmonary or nasal delivery using MDI. The methods described herein include methods for stabilizing formulations comprising LAMA or LABA active substances for respiratory delivery, as well as methods for pulmonary delivery of LAMA and LABA active substances using MDI. Also provided herein are methods of making MDI for delivering an active substance of LAMA or LABA.

In specific embodiments, the methods described herein include methods for treating a lung disease or disorder that is treatable by delivering the active substance LAMA or LABA via MDI. 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 can be used to treat patients suffering from a disease or disorder selected from asthma, chronic obstructive pulmonary disease (COPD), exacerbation of airway hyperresponsiveness due to therapy with another drug, allergic rhinitis , sinusitis, constriction of the vessels of the lungs, inflammation, allergies, shortness of breath, respiratory distress syndrome, pulmonary hypertension, constriction of the vessels of the lungs and any other respiratory disease, condition, trait, genotype or phenotype that may respond to the administration of LAMA or LABA alone or in combination with other methods of therapy. In certain embodiments, the compositions, systems, and methods described herein can be used to treat inflammation and obstruction of the lungs associated with cystic fibrosis. As used herein, the terms “COPD” and “chronic obstructive pulmonary disease” encompass chronic obstructive pulmonary disease (COLD), chronic obstructive airway disease (COAD), chronic airflow restriction (CAL), and chronic obstructive respiratory disease (CORD) and include chronic bronchitis, bronchiectasis, and emphysema. As used herein, the term "asthma" refers to asthma of any type or genesis, including both endogenous (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, severe asthma, exercise-induced asthma due to bronchitis asthma, occupational asthma and asthma induced by bacterial infection. It is also understood that asthma covers childhood asthma syndrome.

It is well understood that the embodiments as described herein are illustrative. The following more detailed description of various embodiments is not intended to limit the scope of the present invention, but is only a typical example of various embodiments. Moreover, the order of the steps or steps in the methods described in relation to the embodiments described herein can be changed by those skilled in the art without departing from the scope of the present invention. In other words, if specific steps or actions are required for the proper effect of the embodiments, the order or application of specific steps or actions can be modified.

I. Definitions

Unless specifically defined otherwise, technical terms, as used herein, have their usual meaning implied in the art. The following terms are defined specifically for clarity.

The term "active substance" is used herein to include any substance, drug, compound, composition or other substance that can be used in humans or animals or administered to humans or animals and is LAMA or LABA. The term “active substance” can be used interchangeably with the terms “drug”, “pharmaceutical agent”, “drug”, “drug substance” or “therapeutic agent”.

The terms “associate,” “associate with,” or “association” refers to the interaction or relationship between a chemical structural unit, composition, or structure in proximity to a surface, such as the surface of another chemical structural unit, composition, or structure. The association includes, for example, adsorption, adhesion, covalent bonding, hydrogen bonding, ionic bonding and electrostatic attraction, Lifshitz-van der Waals interactions and polar interactions. The term “attach” or “adhesion” is an association form and is used as a general term for all forces that tend to cause a particle or mass to attract to the surface. “Attach” also refers to contacting and maintaining the particles in contact with each other so that there is essentially no visible separation between the particles due to their different buoyancy forces in the propellant under normal conditions. In one embodiment, the term “attach” encompasses a particle that is attached to or associated with a surface. Normal conditions may include storage at room temperature or under accelerating force due to gravity. As described herein, particles of the active substance can associate with the suspending particles to form a slurry, where there is essentially no visible separation between the suspending particles and the particles of the active substance or their sediment in the form of flakes due to differences in the buoyancy in the propellant.

"Suspending particles" refers to a material or combination of materials that are acceptable for respiratory delivery and act as a carrier for particles of the active substance. Suspending particles interact with the particles of the active substance, facilitating repeated dosing, delivery or transport of the active substance to a given delivery area, i.e., to the respiratory tract. The suspending particles described herein are dispersed in a suspension medium comprising a propellant or propellant system, and they can be configured in any shape, size or surface characteristics suitable to achieve the desired suspension stability or delivery efficiency of the active substance. Illustrative suspending particles include particles that have a particle size that facilitates the delivery of the active substance to the respiratory tract and that have physical configurations suitable for the manufacture and delivery of stabilized suspensions as described herein.

The term "co-suspension" refers to the suspension of two or more types of particles having different compositions in a suspension medium where particles of the same type are associated at least partially with particles of one or more other types. The association leads to a detectable change in one or more characteristics of at least one of the individual types of particles suspended in a suspension medium. Characteristics modified by the association may include, for example, one or more of the aggregation or settling rate in the form of flakes, the speed or nature of the separation, i.e. sedimentation or delamination, the density of the exfoliated layer or precipitate, adhesion to the walls of the container, adhesion to the components of the valve and the speed and level of dispersion with shaking.

Illustrative methods for evaluating whether a slurry is present include the following: if one type of particle has a pycnometric density greater than the pycnometric density of the propellant and another type of particle has a pycnometric density lower than the pycnometric density of the propellant, a visual examination of the nature of delamination or settling can be used to determine the presence of cosuspension. The term "pycnometric density" refers to the density of the material of which the particle is composed, with the exception of voids in the particle. In one embodiment, the materials can be made and transferred to a transparent bottle, typically a glass bottle, for visual examination. After the initial shaking, the bottle is left without touching for a sufficient time to form a precipitate or exfoliated layer, usually 24 hours. If a precipitate or exfoliated layer is observed as a fully or for the most part homogeneous single layer, then there is a co-suspension. The term "co-suspension" includes partial co-suspension, where most of the at least two types of particles are associated with each other, however, some separation (i.e., less than most) of the at least two types of particles may be observed.

An illustrative test of cosuspension can be carried out at different temperatures of the propellant, paying attention to the nature of sedimentation or delamination of types of particles with a density close to the density of the propellant at room temperature. If different types of particles have the same character of separation, i.e. they all precipitate or all exfoliate, the presence of slurry can be determined by measuring other characteristics of the suspension, such as the rate of aggregation or precipitation in the form of flakes, the separation rate, the density of the exfoliated layer or layer of sediment, adhesion to the walls of the container, adhesion to valve components and the speed and level of dispersion by shaking, and comparing them with the corresponding characteristics of similarly suspended individual types of particles. Various analytical methods commonly known to those skilled in the art can be used to measure these characteristics.

In the context of a composition containing or providing respirable aggregates, particles, drops, etc., such as the compositions described herein, the term “fine particle dose” or “FPD” refers to a dose, or as a total weight , either as part of a nominal dose or a metered dose that is in a respirable range. A dose that is within the respirable range is defined in vitro as the dose that is deposited beyond the nozzle stage in a cascade impactor, i.e. the amount of dose delivered through cascades from 3 to the filter in a Next Generation Impactor impactor operating at a flow rate of 30 l / min.

In the context of a composition containing or providing respirable aggregates, particles, drops, etc., such as the composition described herein, the term “fine particle fraction” or “FPF” refers to the proportion of material delivered relative to the delivered dose (t ie, the amount that leaves the drive mechanism of the delivery device, such as MDI), which is within the respirable range. The amount of material delivered in a respirable range is defined in vitro as the amount of material that accumulates behind the nozzle stage in a cascade impactor, i.e. the amount of dose delivered after 3 stages through a filter in a Next Generation Impactor impactor operating at a flow rate of 30 l / min.

As used herein, the term “inhibits” refers to a measurable reduction in the tendency for a phenomenon, symptom or condition, or the degree to which the phenomenon, symptom or condition occurs. The term "inhibits" or any form thereof is used in its broadest sense, and it includes minimization, prevention, reduction, deterrence, suppression, suspension, limitation, retention, retardation of progression, and the like.

"Mass median aerodynamic diameter" or "MMAD" as used herein refers to the aerodynamic diameter of an aerosol below which 50% of the mass of the aerosol consists of particles with an aerodynamic diameter smaller than MMAD, where the MMAD is calculated according to the monograph 601 United States Pharmacopeia (" USP ").

As used herein, the term "optical diameter" refers to particle size when measured by a Fraunthofer diffraction mode using a laser diffraction particle size analyzer equipped with a dry powder distributor (e.g., Sympatec GmbH, Clausthal-Zellerfeld, Germany).

The term “solution mediated transformation” refers to a phenomenon in which a more soluble form of a solid material (i.e., particles with a small radius of curvature (a driving force for Ostwald ripening), or an amorphous material) dissolves and recrystallizes into a more stable crystalline form, which can coexist in equilibrium with its saturated propellant solution.

"Patient" refers to an animal in which the active substances LAMA or LABA may have a therapeutic effect. In one embodiment, the patient is a human.

“Perforated microstructures” refers to suspending particles that include a structural matrix that exhibits, defines or contains voids, pores, defects, cavities, spaces, pore spaces, slots, openings or recesses that allow the surrounding suspension medium to penetrate, fill or impregnate the microstructure such as the materials and preparations described in US Pat. 6309623 issued by Weers et al. The predominant form of the perforated microstructure is mainly not important, and any final configuration that provides the desired compositional characteristics is provided herein. Thus, in one embodiment, the perforated microstructures may have an approximately spherical shape, such as hollow, spray dried, suspending microspheres. However, flattened, corrugated, deformed, or cracked particulate materials of any prevailing shape or aspect ratio may also be suitable.

As is true for the suspending particles described herein, perforated microstructures 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 particles, in some embodiments, the structural matrix is associated with or includes a surfactant, such as a phospholipid or a fluorinated surfactant. Although not required, incorporating a compatible surfactant in a perforated microstructure or, more commonly, suspending particles, can increase the stability of respiratory dispersions, increase lung deposition, and simplify suspension production.

The term "suspension medium", as used herein, refers to a substance that provides a continuous phase in which the particles of the active substance and suspending particles can be dispersed to form a co-suspension composition. The suspension medium used in the cosuspension compositions described herein includes a propellant.

As used herein, the term “propellant” refers to one or more pharmacologically inert substances that provide a sufficiently high vapor pressure at normal room temperature to move the drug from the MDI container to the patient when the MDI metering valve is actuated. Thus, the term “propellant” refers to both a single propellant and a combination of two or more different propellants forming a “propellant system”.

The term "suitable for inhalation" mainly refers to particles, aggregates, drops, etc., having such a size that they can be inhaled and reach the respiratory tract of the lung.

When used in relation to the co-suspension compositions described herein, the terms “physical stability” and “physically stable” refer to a composition that is resistant to one or more of aggregation, flocculation and particle size changes due to solution-mediated conversion and is capable of essentially retain the MMAD suspending particles and the dose of fine particles. In one embodiment, physical stability can be evaluated by subjecting the composition to accelerated degradation conditions, such as cyclic temperature changes, as described herein.

When referring to active substances, the term "potent" refers to active substances that are therapeutically effective at doses or lower doses ranging from about 0.01 mg / kg to about 1 mg / kg. Typical doses of potent active substances are typically in the range of from about 100 μg to about 100 mg.

When referring to active substances, the term "highly potent" refers to active substances that are therapeutically effective at a dose or below a dose of about 10 μg / kg. Typical doses of highly potent active substances are typically in the range of up to about 100 μg.

The terms "suspension stability" and "stable suspension" refer to suspension compositions capable of preserving the cosuspension properties of the particles of the active substance and the suspending particles over a period of time. In one embodiment, the stability of the suspension can be measured by the uniformity of the delivered dose achieved using the co-suspension compositions described herein.

The term "substantially insoluble" means that the composition is either completely insoluble in a particular solvent, or slightly soluble in this particular solvent. The term “substantially insoluble” means that a particular soluble substance has a solubility of less than one part per 100 parts of solvent. The term “substantially insoluble” includes the definitions of “slightly soluble” (from 100 to 1000 parts of solvent per 1 part of the solute), “very slightly soluble” (from 1000 to 10,000 parts of solvent per 1 part of the dissolved substance), and “practically insoluble” (more than 10,000 parts of solvent per 1 part of solute) as shown in table 16-1 in Remington: The Science and Practice of Pharmacy, 21 st ed. Lippincott, Williams & Wilkins, 2006, p. 212.

The term “surfactant,” as used herein, refers to any substance that is preferably adsorbed on a contact surface between two immiscible phases, such as a contact surface between water and an organic polymer solution, a water / air contact surface or an organic contact surface solvent / air. Surfactants typically have a hydrophilic part and a lipophilic part, so that when adsorbed to microparticles, they tend to provide a continuous phase of groups that do not attract particles with a similar coating, thus reducing particle agglomeration. In some embodiments, surfactants can also provide drug adsorption and increase the bioavailability of the drug.

A “therapeutically effective amount” is an amount of a compound that provides a therapeutic effect by inhibiting a disease or disorder in a patient or by prophylactically inhibiting or preventing the occurrence of a disease or disorder. A therapeutically effective amount may be an amount that alleviates to some extent one or more symptoms of a disease or disorder in a patient; returns to normal, either partially or in full, one or more physiological or biochemical parameters associated with or causing a disease or disorder; and / or reduces the likelihood of a disease or disorder.

The terms “chemically stable” and “chemical stability” refer to co-suspension formulations where individual degradation products of the active substance remain below the limits defined by regulatory requirements over the shelf life of the product for human use (for example, 1% of the total chromatographic peak area according to ICH guidelines Q3B (R2)) and there is an acceptable mass balance (for example, as defined in ICH Q1E) between the analyte being active and the overall degradation products.

II. Pharmaceutical Compositions

The compositions described herein are co-suspensions that include a suspension medium comprising a propellant, particles of the active substance LAMA or LABA, and suspending particles. Of course, if desired, the compositions described herein may include one or more additional components. Moreover, variations and combinations of the compositions of the components described herein can be used. For example, two or more types of suspending particles can be used in the compositions for the manufacture and delivery of the selected active substance LAMA or LABA. Alternatively, for example, the compositions described herein may include two or more types of particles of the active substance. In certain such embodiments, the compositions may include LAMA or LABA active substance particles suspended with suspending particles, where, in addition to the active substance material included in the active substance particles, at least some of the suspending particles include the selected LAMA or LABA active substance. Moreover, if desired, the compositions described herein may include two or more different types of particles containing the selected active substance LAMA or LABA in combination with two or more different types of suspending particles.

It has been found that in the compositions according to the present description, the particles of the active substance exhibit an association with the suspending particles, so that the separation of the particles of the active substance from the suspending particles is essentially prevented, which leads to the co-location of the particles of the active substance and the suspending particles in a suspension medium. As a rule, due to differences in density between different types of particles and the medium in which they are suspended (for example, a propellant or a propellant system), buoyancy forces exfoliate particles with a lower density than the propellant, and sediment particles with a higher density than at the propellant. Thus, it is expected that in suspensions, which include a mixture of particles that vary in their density, the nature of the sedimentation or delamination of each type of particle can vary and can lead to the separation of different types of particles in the propellant.

However, combinations of the propellant, particles of the active substance and suspending particles described herein provide co-suspensions, where the particles of the active substance and suspending particles described herein provide co-suspensions, where the particles of the active substance and suspending particles are together in the propellant (i.e. ., the particles of the active substance are associated with suspending particles, so that the suspending particles and particles of the active substance do not show significant separation from each other, e.g. Emer, characterized by sedimentation or peeling even after a period of time sufficient to scaling or fouling). In specific embodiments, for example, the compositions described herein form co-suspensions where the suspending particles remain associated with the particles of the active substance under buoyancy forces amplified due to temperature fluctuations and / or centrifugation under accelerations up to, for example, above 1 g, 10 g, 35 g, 50 g and 100 g. However, the co-suspensions described herein are not necessarily determined or limited to a particular association threshold strength. For example, it is possible to successfully obtain the co-suspension provided herein where particles of the active substance are associated with suspending particles, so that there is essentially no significant separation of the particles of the active substance and suspending particles in the continuous phase formed by the suspension medium under typical conditions of use by the patient.

Co-suspension compositions according to the present description provide the desired characteristics of the composition and delivery of active substances LAMA and LABA. For example, in certain embodiments, when cosuspensions, as described herein, are in an MDI container, they can inhibit or reduce one or more of the following: flocculation of the material of the active substance; differential sedimentation or delamination of the particles of the active substance and suspendida particles; solution-mediated conversion of the material of the active substance; and loss of active substance on the surfaces of the capping system of the container, in particular on the components of the metering valve. In addition, the compositions described herein provide chemical stability to the active substances contained therein. The effect of these qualities is the provision and preservation of aerosol characteristics during the delivery of cosuspension from MDI, so that the desired characteristics of the fine particle fraction, dose of fine particles and uniformity of the delivered dose are ensured and are essentially maintained throughout the emptying of the MDI container in which the cosuspension composition is contained. In addition, as illustrated by the embodiments described in detail herein, co-suspensions as described herein can provide a stable formulation that provides appropriate dosage and respiratory delivery characteristics of the active substances LAMA and LABA, while using a relatively simple HFA suspension medium that does not requires modification by the addition of, for example, cosolvents, antisolvents, solubilizing agents or adjuvants.

The presentation of a co-suspension as described herein may also simplify the manufacture, delivery and dosage of the active substances LAMA and LABA. Without being bound by a particular theory, it is believed that by providing a co-suspension of the particles of the active substance and the suspending particles, the delivery and dosage of the active substance contained in such a dispersion can be substantially controlled by controlling the size, composition, morphology and relative amount of the suspending particles, and it is less depends on the size and morphology of the particles of the active substance.

Thus, the pharmaceutical compositions described herein provide for the delivery of the active substances LAMA and LABA from MDI. Delivery of the co-suspension compositions described herein provides the desired pharmacokinetic and pharmacodynamic characteristics, and MDI delivery of the pharmaceutical compositions described herein is useful for treating patients suffering from an inflammatory or obstructive disease or lung condition that responds to the administration of the active substance LAMA or LABA. In specific embodiments, the pharmaceutical compositions described herein can be used to treat a disease or condition selected from asthma, COPD, exacerbation of airway hyperresponsiveness due to other drug therapy, allergic rhinitis, sinusitis, constriction of the blood vessels of the lungs, inflammation, allergies, difficulty breathing, respiratory distress syndrome, pulmonary hypertension, narrowing of the vessels of the lungs and any other respiratory disease, condition, symptom, genotype Whether phenotype, which can answer to the introduction LAMA or LABA, alone or in combination with other therapies. In certain embodiments, the compositions, systems, and methods described herein can be used to treat inflammation and obstruction of the lungs associated with cystic fibrosis.

(i) Suspension medium

The suspension medium included in the composition described herein includes one or more propellants. Typically, suitable propellants for use as suspension media are propellant gases that can be liquefied under pressure at room temperature, and when inhaled or applied topically, are safe and toxicologically harmless. In addition, it is desirable that the selected propellant be relatively unreactive with respect to suspending particles or particles of the active substance. Illustrative compatible propellants include hydrofluoroalkanes (HFAs), perfluorinated compounds (PFCs) and chlorofluorocarbons (CFCs).

Specific examples of propellants that can be used to form the slurry suspension media described herein include 1,1,1,2-tetrafluoroethane (CF ₃ CH ₂ F) (HFA-134a), 1,1,1,2,3 , 3,3-heptafluoro-n-propane (CF ₃ CHFCF ₃ ) (HFA-227), perfluoroethane, monochlorofluoromethane, 1,1-difluoroethane and combinations thereof. Moreover, suitable propellants include, for example: short chain hydrocarbons; C _1-4 hydrogen-containing chlorofluorocarbons such as CH ₂ ClF, CCl ₂ FCHClF, CF ₃ CHClF, CHF ₂ CClF ₂ , CHClFCHF ₂ , CF ₃ CH ₂ Cl, and CClF ₂ CH ₃ ; C _1-4 hydrogen-containing fluorocarbons (e.g., HFA) such as CHF ₂ CHF ₂ , CF ₃ CH ₂ F, CHF ₂ CH ₃ and CF ₃ CHFCF ₃ ; and perfluorocarbons such as CF ₃ CF ₃ and CF ₃ CF ₂ CF ₃ .

Specific fluorocarbons or classes of fluorinated compounds that can be used as a suspension medium include, but are not limited to, fluoroheptane, fluorocycloheptane, fluoromethylcycloheptane, fluorohexane, fluorocyclohexane, fluoropentane, fluorocyclopentane, fluoromethylcyclopentane, fluoromethylobutane, fluorocyclobutane, fluoropropane, fluorine-containing ethers, fluorine-containing polyethers and fluorotriethylamines. These compounds can be used alone or in combination with more volatile propellants.

In addition to the above fluorocarbons and hydrofluoroalkanes, various illustrative chlorofluorocarbons and substituted fluorinated compounds can also be used as a suspension medium. In this regard, 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), taking into account possible environmental considerations. Essentially, each of these compounds can be used individually or in combination with other compounds (i.e., less volatile fluorocarbons) to form the stabilized suspensions described herein.

In some embodiments, a suspension medium may be formed with a single propellant. In other embodiments, a combination of propellants (“propellant system”) can be used to form a suspension medium. In some embodiments, relatively volatile compounds can be mixed with lower vapor pressure components to provide a suspension medium having certain physical characteristics selected from increased stability or increased bioavailability of the dispersed active substance. In some embodiments, lower vapor pressure compounds comprise fluorinated compounds (eg, fluorocarbons) having a boiling point of greater than about 25 ° C. In some embodiments, lower vapor pressure fluorinated compounds for use in a suspension medium may include C ₈ F ₁₇ Br perfluorooctyl bromide (PFOB or Perflubron), C ₈ F ₁₆ Cl ₂ dichlorofluorooctane, C ₈ F ₁₇ C ₂ H ₅ perfluorooctyl ethane (PFOE) , perfluorodecyl bromide C ₁₀ F ₂₁ Br (PFDB) or perfluorobutyl ethane C ₄ F ₉ C ₂ H ₅ . In certain embodiments, these compounds with lower vapor pressure are present at a relatively low level. Such compounds can be added directly to the suspension medium, or they can be associated with suspending particles.

The suspension medium included in the compositions described herein may be formed from a propellant or propellant system that is substantially free of additional materials, including, for example, anti-solvents, solubilizing agents, cosolvents or adjuvants. For example, in some embodiments, the suspension medium may be formed from a non-CFC propellant or propellant system, such as an HFA-based propellant or propellant system, which is substantially free of additional materials. Such embodiments simplify the preparation and manufacture of pharmaceutical compositions suitable for respiratory delivery of the active substance LAMA or LABA.

However, in other embodiments, depending on the choice of propellant, the properties of the suspending particles, or the nature of the active substance to be delivered, the suspension medium used may include materials in addition to the propellant or propellant system. Such additional materials may include, for example, one or more suitable anti-solvents, solubilizing agents, cosolvents or adjuvants, for example, to correct, for example, vapor pressure of the composition, or stability or solubility of suspended particles. For example, propane, ethanol, isopropyl alcohol, butane, isobutane, pentane, isopentane or a dialkyl ether such as dimethyl ether can be included in a propellant suspension medium. Similarly, the suspension medium may contain volatile fluorocarbon. In other embodiments, one or both of polyvinylpyrrolidone ("PVP") or polyethylene glycol ("PEG") can be added to the suspension medium. Adding PVP or PEG to the suspension medium can provide one or more desired functional characteristics, and, in one example, PVP or PEG can be added to the suspension medium as an inhibitor of crystal growth. Typically, when a volatile cosolvent or adjuvant is used, such an adjuvant or cosolvent can be selected from known hydrocarbon or fluorocarbon materials, and they can be up to about 1% v / v. suspension medium. For example, when a co-solvent or adjuvant is included in the suspension medium, the co-solvent or adjuvant may be less than about 0.01%, 0.1% or 0.5% w / w. suspension medium. When PVP or PEG is included in the suspension medium, such components may be included in an amount up to about 1% w / w, or they may be less than about 0.01%, 0.1%, or 0.5% w. / mass suspension medium.

(ii) Particles of the active substance

The particles of the active substance included in the suspension, described herein, are formed so that they can be dispersed or suspended in a suspension medium, and they are sized to facilitate the delivery of respirable particles from the suspension. Thus, in one embodiment, the particles of the active substance are provided as micronized material, where at least 90% of the material of the particles of the active substance by volume exhibit an optical diameter of 7 μm or less. In other embodiments, the implementation of the particles of the active substance is provided as a micronized material, where at least 90% of the particles of the active substance by volume exhibit an optical diameter selected from the range from about 6 microns to about 1 microns, from about 5 microns to about 2 microns, and from about 4 microns to about 3 microns. In further embodiments, the particles of the active substance are provided as micronized material, wherein at least 90% of the particles of the active substance by volume exhibit an optical diameter selected from 6 μm or less, 5 μm or less and 4 μm or less. In another embodiment, the particles of the active substance are provided as micronized material, wherein at least 50% of the material of the particles of the active substance by volume exhibit an optical diameter of about 5 μm or less. In other embodiments, implementation of the particles of the active substance is provided as a micronized material, where at least 50% of the active substance by volume exhibit an optical diameter selected from a range of from about 4 μm to about 1 μm, from about 3 μm to about 1 μm, and about 2.5 microns to about 1 microns. In another embodiment, the active substance particles are provided as micronized material, wherein at least 50% of the active substance particles by volume exhibit an optical diameter selected from 4 μm or less, 3 μm or less, and 2 μm or less.

In specific embodiments, the material of the active substance used as particles of the active substance or for their formation can be completely or essentially crystalline, i.e. most of the molecules of the active substance are arranged in a regular repeating pattern over a large area or along the planes of the outer surface. In another embodiment, the particles of the active substance may include the active substance present in both crystalline and amorphous states. In another embodiment, particles of the active substance may be present in both crystalline and amorphous states. In another embodiment, particles of the active substance may be present in a substantially amorphous state, i.e. the nature of the particles of the active substance is completely non-crystalline and does not have a regularly repeating arrangement of molecules that lasts over a large area. Suitable excipients for the manufacture of particles of the active substance include excipients described herein with reference to suspendida particles. In specific embodiments, implementation, for example, particles of the active substance can be made with one or more of lipids, phospholipids, carbohydrates, amino acids, organic salts, peptides, proteins, alditols, synthetic or natural polymers or surface-active materials, as described, for example, in relation to suspending particles. In other embodiments, implementation of the particles of the active substance is formed only from the material of the micronized active substance.

Because the compositions described provide for the manufacture and reproducible delivery of very low doses of the active substance, in certain embodiments, the active substance included in the compositions described herein may be selected from one or more potent or potent active substances. For example, in certain embodiments, the compositions described herein may include a potent active substance that is delivered in a unit dosage, selected from about 100 μg to about 100 mg per dose, from about 100 μg to about 10 mg per dose, and from about 100 μg to 1 mg per dose. In other embodiments, the compositions described herein may include a potent or highly potent active substance, which is delivered in a dose selected from up to about 80 μg per unit dose, up to about 40 μg per unit dose, up to about 20 micrograms per single administration dose, or from about 10 micrograms to about 100 micrograms per single administration dose. In addition, in certain embodiments, the compositions described herein may include a potent active substance delivered in a dose selected from about 0.1 to about 2 μg per unit dose, from about 0.1 to about 1 μg per a single administration dose, and from about 0.1 to about 0.5 μg per single administration dose.

In certain embodiments, the active substance included in the compositions described herein is an LAMA active substance. When the compositions comprise an active LAMA, in specific embodiments, the active LAMA may be selected, for example, from glycopyrrolate, dixipyrronium, tiotropium, trospium, aklidinium, darotropy, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof.

Glycopyrrolate can be used to treat inflammatory or obstructive diseases and lung disorders, such as the diseases and lung disorders described herein. As an anticholinergic agent, glycopyrrolate acts as a bronchodilator and provides an antisecretory effect, which is useful for the treatment of diseases and disorders of the lungs, characterized by increased secretion of mucus. Glycopyrrolate is a quaternary ammonium salt. When appropriate, glycopyrrolate can be used in the form of salts (for example, alkali metal or amine salts or as acid addition salts) or as esters or as solvates (hydrates). In addition, the glycopyrrolate may be in any crystalline form or isomeric form or a mixture of isomeric forms, for example, in the form of a pure enantiomer, a mixture of enantiomers, a racemate, or a mixture thereof. In this regard, the glycopyrrolate form can be chosen so as to optimize the activity and / or stability of the glycopyrrolate and / or to minimize the solubility of the glycopyrrolate in suspension medium. Suitable counterions are pharmaceutically acceptable counterions, including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl acetate or triphenyl acetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxy-naphthalene-2-carboxylate, 3-hydroxy-naphthalene-2-carboxylate, methanesulfonate and benzenesulfonate. In specific embodiments of the compositions described herein, glycopyrrolate bromide is used, namely 3 - [(cyclopentylhydroxyphenylacetyl) oxy] -1,1-dimethylpyrrolidinium bromide and can be prepared by methods described in US Pat. 2956062.

When the compositions described herein include glycopyrrolate, in certain embodiments, the compositions may include enough glycopyrrolate to provide a given delivery dose selected from about 10 μg to about 200 μg per MDI actuation, from about 15 μg to about 150 μg on the actuation of MDI, and from about 18 mcg to about 144 mcg on the actuation of MDI. In other such embodiments, the compositions include a sufficient amount of glycopyrrolate to provide a dose selected from up to about 200 μg, up to about 150 μg, up to about 75 μg, up to about 40 μg, or up to about 20 μg per actuation. In other embodiments, the compositions include enough glycopyrrolate to provide a dose selected from approximately 18 μg per actuation, 36 μg per actuation, or approximately 72 μg per actuation. In order to achieve the desired delivered doses, as described herein, where the compositions described herein include glycopyrrolate as an active substance, in specific embodiments, the amount of glycopyrrolate included in the compositions may be selected, for example, from about 0.04 mg / ml to about 2.25 mg / ml.

In other embodiments, tiotropium, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, may be selected as the LAMA active substance for inclusion in the composition as described herein. Tiotropium is a known long-acting anticholinergic drug suitable for use in the treatment of diseases or disorders associated with pneumonia or obstruction of the lungs, such as the diseases or disorders described herein. Tiotropium, including crystalline forms and forms of pharmaceutically acceptable salts of tiotropium, are described, for example, in US Pat. 5610163, US patent No. RE39820, US Pat. 6777423 and U.S. Pat. 6908928. When the compositions described herein include tiotropium, in certain embodiments, the compositions may include enough tiotropium to provide a delivered dose selected from about 2.5 μg to about 50 μg, about 4 μg to about 25 μg, and from about 2.5 μg to about 20 μg, from about 10 μg to about 20 μg, and from about 2.5 μg to about 10 μg per actuation of MDI. In other such embodiments, the compositions include sufficient tiotropium to provide a delivered dose selected from up to about 50 μg, up to about 20 μg, up to about 10 μg, up to about 5 μg, or up to about 2.5 μg per cast into action MDI. In other embodiments, the compositions include sufficient tiotropium to provide a delivered dose selected from approximately 3 μg, 6 μg, 9 μg, 18 μg, and 36 μg to drive the MDI. To provide deliverable doses, as described herein, where the compositions described herein include tiotropium as an active substance, in specific embodiments, the amount of tiotropium included in the compositions may be selected, for example, from about 0.01 mg / ml to about 0.5 mg / ml.

In certain embodiments, the compositions described herein comprise the active substance LABA. In such embodiments, the LABA active substance may be selected from, for example, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol and saligenin or indole-containing β ₂ agonists and β ₂ agonists derived from adamantyl and their any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In certain such embodiments, formoterol is selected as the active substance LABA. Formoterol can be used to treat inflammatory or obstructive diseases or lung disorders, for example, such as the diseases and disorders described herein. Formoterol has the chemical name (±) -2-hydroxy-5 - [((1RS) -1-hydroxy-2 - [[(1RS) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] formanilide, and it is usually used in pharmaceutical compositions as the racemic fumarate salt dihydrate. When appropriate, formoterol can be used in the form of salts (for example, alkali metal or amine salts or as acid addition salts) or as esters or as solvates (hydrates). In addition, formoterol can be in any crystalline form or isomeric form or a mixture of isomeric forms, for example, in the form of a pure enantiomer, a mixture of enantiomers, a racemate, or a mixture thereof. In this regard, the form of formoterol can be chosen so as to optimize the activity and / or stability of formoterol and / or to minimize the solubility of formoterol in a suspension medium. Pharmaceutically acceptable salts of formoterol include, for example, salts of inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids such as fumaric, maleic, acetic, lactic, citric, tartaric, ascorbic, succinic, glutaric, gluconic, tricarboxylic , oleic, benzoic, p-methoxybenzoic, salicylic, o- and p-hydroxybenzoic, p-chlorobenzoic, methanesulfonic, p-toluenesulfonic and 3-hydroxy-2-naphthalene carboxylic acids. Formoterol hydrates are described, for example, in US Pat. 3994974 and U.S. Pat. 5684199. Specific crystalline forms of formoterol and other β ₂ -adrenergic receptor agonists are described, for example, in WO95 / 05805, and specific isomers of formoterol are described in US Pat. 6040344.

In specific embodiments, the formoterol material used to form the formoterol particles is formoterol fumarate, and in one such embodiment, formoterol fumarate is present in the form of a dihydrate. When the compositions described herein include formoterol, in certain embodiments, the compositions described herein may include formoterol at a concentration that reaches a predetermined delivery dose selected from about 1 μg to about 30 μg, from about 1 μg to about 10 μg, from about 2 μg to about 5 μg, from about 2 μg to about 10 μg, from about 5 μg to about 10 μg, and from 3 μg to about 30 μg per e in MDI operation. In other embodiments, the compositions described herein may include formoterol in an amount sufficient to provide a given delivered dose 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 per actuation. In order to achieve the desired delivered doses, as described herein, where the compositions described herein include formoterol as an active substance, in specific embodiments, the amount of formoterol included in the compositions may be selected, for example, from about 0.01 mg / ml to about 1 mg / ml, from about 0.01 mg / ml to about 0.5 mg / ml, from about 0.03 mg / ml to about 0.4 mg / ml.

When the pharmaceutical antisuspension compositions described herein comprise the LABA active substance, in certain embodiments, the active substance may be salmeterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. Salmeterol can be used to treat inflammatory or obstructive diseases and lung disorders, for example, such as the diseases and disorders described herein. Salmeterol, pharmaceutically acceptable salts of salmeterol, and methods for their preparation are described, for example, in US Pat. 4992474, U.S. Pat. 5126375 and U.S. Patent 5,225,445.

When salmeterol is included as an active substance of LABA, in certain embodiments, the compositions described herein may include salmeterol in a concentration that provides a delivered dose selected from about 2 μg to about 120 μg, from about 4 μg to about 40 μg from about 8 μg to about 20 μg, from about 8 μg to about 40 μg, from about 20 μg to about 40 μg, and from 12 μg to about 120 μg per actuation MD I. In other embodiments, the compositions described herein may include salmeterol in an amount sufficient to provide a delivered dose selected from up to about 120 μg, up to about 40 μg, up to about 20 μg, up to about 10 μg, up to up to about 8 μg, or up to about 6 μg per actuation of MDI. In order to achieve the desired delivered doses, as described herein, where the compositions described herein include salmeterol as an active substance, in specific embodiments, the amount of salmeterol included in the compositions can be selected, for example, from about 0.04 mg / ml to about 4 mg / ml, from about 0.04 mg / ml to about 2.0 mg / ml, from about 0.12 mg / ml to about 0.8 mg / ml. For example, the compositions described herein may include enough salmeterol to provide a given delivered dose, selected from about 4 μg to about 120 μg, from about 20 μg to about 100 μg, from about 40 μg to about 120 μg per cast MDI action. In other embodiments, the compositions described herein may include enough salmeterol to provide a given delivered dose, selected from up to about 100 μg, up to about 40 μg, or up to about 15 μg per MDI actuation.

Although the active substance material included in the compositions described herein may be amorphous or substantially amorphous, in specific embodiments, the active substance material used as or for forming particles of the active substance included in the compositions described herein is substantially or completely crystalline. The material of the active substance, which is essentially or completely crystalline, can be selected so as to increase the chemical stability of the active substance LAMA or LABA in the manufacture of the compositions described herein. Thus, in specific embodiments, the active material material included in the compositions described herein is a micronized crystalline LAMA material. In one such embodiment, the particles of the active substance are formed only from micronized crystalline LAMA material, such as a micronized crystalline material selected from glycopyrrolate, dexypyrronium, tiotropium, trospium, aclidinium, darotropy and any pharmaceutically acceptable salts, esters or solvates thereof. In other specific embodiments, the implementation of the material of the active substance included in the compositions described herein is a micronized crystalline material LABA. In one such embodiment, the particles of the active substance are formed only from micronized crystalline LABA material, such as a micronized crystalline material selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol and saligenin- or indole-containing β ₂ -agonists and β ₂ agonists derived from adamantyl and any pharmaceutically acceptable salts, esters or solvates thereof.

Any suitable process may be used to prepare the micronized active material as particles of the active substance or in the manufacture of particles of the active substance included in the compositions described herein. A variety of processes can be used to produce active substance particles suitable for use in the slurry formulations described herein, including, but not limited to, micronization using grinding or grinding processes, crystallization or recrystallization processes, and processes using supercritical deposition or substantially supercritical solvents, spray drying, spray lyophilization or lyophilization. Patent references that describe suitable methods for preparing micronized particles of the active substance include, for example, US Pat. 6063138, U.S. Pat. 5858410, U.S. Pat. 5851453 U.S. Pat. 5833891, U.S. Pat. 5707634, and international patent publication No. WO 2007/009164. When the active substance particles include an active substance material made with one or more excipients or adjuvants, micronized particles of the active substance can be formed using one or more of the preceding processes, and such processes can be used to obtain active substance particles having a desired particle size distribution and particle configuration.

(iii) Suspending particles

Suspending particles included in the antisuspension compositions described herein act to promote stabilization and delivery of the active substance included in the compositions. Although various forms of suspending particles can be used, suspending particles are generally formed from a pharmacologically inert material that is acceptable for inhalation and is substantially insoluble in the selected propellant. Generally, most suspending particles are sized in a respirable range. In specific embodiments, the implementation, therefore, MMAD suspendida particles does not exceed approximately 10 microns, but is not lower than approximately 500 nm. In an alternative embodiment, the MMAD of the suspending particles is from about 5 microns to about 750 nm. In another embodiment, the MMAD of the suspending particles is from about 1 μm to about 3 μm. In one embodiment, when used for nasal delivery from MDI, the MMAD of the suspending particles is from 10 μm to 50 μm.

To provide respirable suspending particles in the described MMAD ranges, suspending particles typically exhibit a volumetric average optical diameter of from about 0.2 microns to about 50 microns. In one embodiment, the suspending particles exhibit a volumetric average optical diameter that does not exceed about 25 microns. In another embodiment, the suspending particles exhibit a volume average optical diameter selected from from about 0.5 microns to about 15 microns, from about 1.5 microns to about 10 microns, and from about 2 microns to about 5 microns.

The concentration of the suspending particles included in the composition according to the present invention can be adjusted, for example, depending on the number of particles of the active substance and the suspension medium used. In one embodiment, the suspending particles are included in the suspension medium at a concentration selected from from about 1 mg / ml to about 15 mg / ml, from about 3 mg / ml to about 10 mg / ml, from 5 mg / ml to about 8 mg / ml, and approximately 6 mg / ml. In another embodiment, suspending particles are included in the suspension medium at a concentration of up to about 30 mg / ml. In another embodiment, suspending particles are included in the suspension medium at a concentration of up to about 25 mg / ml.

The relative amount of suspending particles relative to the particles of the active substance is chosen so as to provide the co-suspension provided herein. It is possible to provide a co-suspension composition, where the amount of suspending particles, measured by weight, exceeds the number of particles of the active substance. For example, in specific embodiments, the ratio of the total weight of the suspending particles to the total particle weight of the active substance may be from about 3: 1 to about 15: 1, or alternatively from about 2: 1 to about 8: 1. Alternatively, the ratio of the total weight of the suspending particles to the total particle weight of the active substance may be about 1, for example up to about 1.5, up to about 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, depending imosti the nature of the suspending particles and particles of active substance. In the following embodiments, the ratio of the total mass of the suspending particles to the total particle weight of the active substance can be selected from from about 10 to about 200, from about 60 to about 200, from about 15 to about 60, from about 15 to about 170, from about 15 to about 60, about 16, about 60, and about 170.

In other embodiments, the amount of suspending particles, measured by weight, is less than the number of particles of the active substance. For example, in specific embodiments, the weight of the suspending particles may be up to 20% of the total particle weight of the active substance. However, in some embodiments, the total mass of the suspending particles may also be approximately equal to or equal to the total mass of the particles of the active substance.

Suspending particles suitable for use in the compositions described herein may be formed from one or more pharmaceutically acceptable materials or excipients that are suitable for inhaled delivery and substantially do not degrade or dissolve in a suspension medium. In one embodiment, perforated microstructures as defined herein may be used as suspending particles. Illustrative excipients that can be used in the suspending particles described herein include, but are not limited to, (a) carbohydrates, for example, monosaccharides such as fructose, galactose, glucose, D-mannose, sorbose, and the like. ; disaccharides such as sucrose, lactose, trehalose, cellobiose and the like; cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin; and polysaccharides such as raffinose, maltodextrins, dextrans, starches, chitin, chitosan, inulin and the like; (b) amino acids such as alanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, lysine, leucine, isoleucine, valine, and the like; (c) metal salts and organic salts derived from organic acids and bases, such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride and the like; (d) peptides and proteins, such as aspartame, trileucine, human serum albumin, collagen, gelatin and the like; (e) alditols such as mannitol, xylitol and the like; (f) synthetic or natural polymers or combinations thereof, such as polylactides, copolymers of lactides and glycolides, cyclodextrins, polyacrylates, methyl cellulose, carboxymethyl cellulose, polyvinyl alcohols, polyanhydrides, polylactams, polyvinylpyrrolidones, hyaluronic acid, and (g) surfactants, including fluorinated and non-fluorinated compounds, such as saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, and combinations thereof. In specific embodiments, suspending particles may include a calcium salt, such as calcium chloride, as described, for example, in US Pat. 7442388.

In addition, in the preparation of suspending particles suitable for use in the compositions described herein, phospholipids from both natural and synthetic sources can be used. In specific embodiments, the selected phospholipid has a transition from a gel to a liquid crystalline phase at more than about 40 ° C. Illustrative phospholipids are relatively long chain saturated lipids (i.e., C16-C22) and may include saturated phospholipids, such as saturated phosphatidylcholines having an acyl chain length of 16C or 18C (palmitoyl and stearoyl). Illustrative phospholipids include phosphoglycerides, such as dipalmitoylphosphatidylcholine, disterooylphosphatidylcholine, diarachidoylphosphatidylcholine, dibegenoylphosphatidylcholine, long chain saturated chain phosphatidylcholine saturatedhenyl phospholated, saturated fattylated Additional excipients are described in international patent publication No. WO 96/32149 and U.S. Pat. 6358530, 6372258 and 6518239.

In specific embodiments, suspending particles may be formed using one or more lipids, phospholipids, or saccharides, as described herein. In some embodiments, suspending particles include one or more surfactants. The use of suspending particles formed from or incorporating one or more surfactants can activate the absorption of the selected active substance, thereby increasing bioavailability. The suspending particles described herein, for example, such as suspending particles formed using one or more lipids, can be formed so that they exhibit the desired surface roughness (roughness), which can further reduce interactions between particles and increase aerosolization by reducing surface area available for particle-particle interaction. In the following embodiments, if appropriate, for the formation of suspending particles, such as suspending particles, which have the potential to reduce opsonization (and thereby reduce phagocytosis of alveolar macrophages), a lipid that naturally occurs in the lungs can be used, thus , providing long-term controlled release of particles in the lung.

In another aspect, the suspending particles used in the compositions described herein can be selected to increase storage stability of the selected active substance, similarly to the suspending particles described in international patent publication No WO 2005/000267. For example, in one embodiment, the suspending particles may include pharmaceutically acceptable glassy stabilizing excipients having a Tg of at least 55 ° C, at least 75 ° C, or at least 100 ° C. Glass former suitable for use in the compositions described herein include, but are not limited to, one or more of trileucine, sodium citrate, sodium phosphate, ascorbic acid, inulin, cyclodextrin, polyvinylpyrrolidone, mannitol, sucrose, trehalose, lactose, and proline . Examples of additional glass-forming excipients are described in US Pat. RE 37872, 5928469, 6258341.

Suspending particles can be developed, given the size and shape, if desired, to provide the desired stability and delivery characteristics of the active substance. In one illustrative embodiment, the suspending particles comprise perforated microstructures as described herein. When perforated microstructures are used as suspending particles in the compositions described herein, they can be formed using one or more excipients, as described herein. For example, in specific embodiments, perforated microstructures may include at least one of the following: lipids, phospholipids, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants, and combinations thereof, in particular, approved for pulmonary use. Specific surfactants that can be used to prepare perforated microstructures include poloxamer 188, poloxamer 407, and poloxamer 338. Other specific surfactants include oleic acid or its alkaline salts. In one embodiment, perforated microstructures comprise more than about 10% v / v. surfactant.

In some embodiments, suspending particles can be prepared by forming an oil-in-water emulsion using fluorocarbon oil (eg, perfluorooctyl bromide, perfluorodecalin), which can be emulsified using a surfactant such as a long chain saturated phospholipid. Then, the resulting perfluorocarbon emulsion in water can be processed using a high pressure homogenizer that reduces the size of oil droplets. The perfluorocarbon emulsion can be fed to a spray dryer, optionally with a solution of the active substance, if it is desired to include the active substance in a matrix of perforated microstructures. As is well known, spray drying is a one-step process that turns liquid feed into a dried form of particles. Spray drying is used to produce powdered pharmaceutical material for various routes of administration, including inhalation. The operating conditions of the spray dryer (such as inlet and outlet temperatures, feed rate, spray pressure, flow rate of drying air and nozzle configuration) can be adjusted to obtain the desired particle size to obtain the outputs of the final dry microstructures. Such methods for preparing illustrative perforated microstructures are described in US Pat. 6309623 issued by Weers et al.

Perforated microstructures, as described herein, can also be formed by lyophilization and subsequent grinding or micronization. Lyophilization is a freeze-drying process in which water is sublimated from the composition after it is frozen. This process allows drying without increasing temperatures. In other embodiments, suspending particles may be prepared using a spray lyophilization process, such as described in US Pat. No. 5,727,333.

Moreover, suspending particles, as described herein, may include fillers, such as polymer particles. The polymer particles may be formed from biocompatible and / or biodegradable polymers, copolymers or mixtures. In one embodiment, polymers capable of forming aerodynamically light particles, such as functionalized polyester grafted copolymers and biodegradable polyanhydrides, can be used. For example, bulk disintegrating polyesters based on polyesters, including poly (hydroxy acids), can be used. Polyglycolic acid (PGA), polylactic acid (PLA) or their copolymers can be used to form suspending particles. The polyester may include a charged or functionalizable group, such as an amino acid. For example, suspending particles can be formed from poly (D, L-lactic acid) and / or a copolymer of D, L-lactic and glycolic acid (PLGA), which include a surfactant such as DPPC.

Other potential candidate polymers for use in suspending particles may include polyamides, polycarbonates, polyalkylenes such as polyethylene, polypropylene, polyethylene glycol, poly (ethylene oxide), poly (ethylene terephthalate), polyvinyl compounds such as polyvinyl alcohols, polyvinyl ethers and polyvinyl esters, polymers of acrylic and methacrylic acids, cellulose and other polysaccharides, and peptides or proteins, or their copolymers or mixtures thereof. The polymers can be selected or modified so that they have suitable stability and in vivo degradation rates for various applications for controlled drug delivery.

The compositions described herein may include two or more types of suspending particles. Moreover, the compositions according to the present description may include suspendida particles, which include glycopyrrolate included in the suspension particles. When the active substance is included in the suspending particles, the suspending particles can be respirable in size, and they can be manufactured and produced using, for example, the methods and materials described herein.

Compositions made as described herein can inhibit the degradation of the active substance included in them. For example, in specific embodiments, the compositions described herein inhibit one or more of floc sedimentation, aggregation, and solution-mediated conversion of the material of the active substance included in the composition. The pharmaceutical compositions described herein are suitable for respiratory delivery via MDI in such a way that the delivered dose ("DDU") of the active substances LAMA and LABA, including the potent and potent active substances LAMA and LABA, is maintained throughout the emptying of the MDI container. As described in detail in the examples included herein, even in the case of delivery of very low doses of the active substances LAMA and LABA, the compositions described herein can provide a DDU for the active substance of ± 30% or better throughout the course of emptying the MDI tank. In one such embodiment, the compositions described herein provide a DDU for the active substance of ± 25% or better during the course of emptying the MDI tank. In another such embodiment, the compositions described herein provide a DDU for the active substance of ± 20% or better during the course of emptying the MDI tank.

The pharmaceutical compositions described herein also serve essentially to maintain the characteristics of FPF and FPD during the emptying of the MDI tank, even after exposure to accelerated degradation conditions. For example, the compositions of the present description retain up to 80%, 90%, 95% or more of the original characteristics of FPF and FPD during the emptying of the MDI capacity even after exposure to accelerated degradation conditions. The compositions described herein provide the added benefit of achieving such characteristics in the manufacture of non-CFC propellants. In specific embodiments, the compositions described herein provide one or all of the specified DDU, FPF, and FPD characteristics when manufactured with a suspension medium containing only one or more non-CFC propellants, and without the need to modify the characteristics of the non-CFC propellant, such as by adding, for example, one or more cosolvents, antisolvents, solubilizing agents, adjuvants or other propellant modifying materials.

In one embodiment, a co-suspension composition, as described herein, includes: a suspension medium comprising a pharmaceutically acceptable HFA-based propellant; a plurality of particles of the active substance containing glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in a suspension medium at a concentration sufficient to provide a delivered dose of glycopyrrolate from about 20 μg to about 150 μg per actuation of the metered dose inhaler dose; and a plurality of respirable suspending particles containing perforated microstructures, as described herein, having a volume average optical diameter of from about 1.5 microns to about 10 microns, where the perforated microstructures are associated with a plurality of particles of the active substance to form a co-suspension. In one such embodiment, glycopyrrolate active substance particles are formed from crystalline glycopyrrolate material. In another such embodiment, the ratio of the total mass of the suspending particles to the total particle weight of the active substance is selected from from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1. In another such embodiment, the glycopyrrolate active substance particles are formed from crystalline glycopyrrolate material, and the ratio of the total weight of the suspending particles to the total particle weight of the active substance is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1. In another such embodiment, the glycopyrrolate active substance particles are formed from crystalline glycopyrrolate material, at least 90% of the active glycopyrrolate particles by volume exhibit an optical diameter of less than 7 μm, and the ratio of the total weight of the suspending particles to the total particle weight of the active substance is selected from about 3 : 1 to about 15: 1; and from about 2: 1 to 8: 1.

In another embodiment, the co-suspension composition as described herein includes: a suspension medium comprising a pharmaceutically acceptable HFA-based propellant; a plurality of particles of the active substance containing tiotropium, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in a suspension medium in a concentration sufficient to provide a delivered dose of glycopyrrolate from about 5 μg to about 40 μg per actuation of the metered-dose inhaler dose; and a plurality of respirable suspending particles containing perforated microstructures, as described herein, having a volume average optical diameter of from about 1.5 microns to about 10 microns, where the perforated microstructures are associated with a plurality of particles of the active substance to form a co-suspension. In one such embodiment, the tiotropium active substance particles are formed from crystalline tiotropium material. In another such embodiment, the ratio of the total mass of the suspending particles to the total particle weight of the active substance is selected from from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1. In another such embodiment, the particles of the active substance tiotropium are formed from crystalline tiotropium material, and the ratio of the total mass of the suspending particles to the total mass of particles of the active substance is selected from from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1. In another such embodiment, the tiotropium active substance particles are formed from tiotropium crystalline material, at least 90% of the tiotropium active substance particles by volume exhibit an optical diameter of less than 7 μm, and the ratio of the total mass of the suspending particles to the total mass of the active substance particles is selected from from about 3 : 1 to about 15: 1; and from about 2: 1 to 8: 1.

In another embodiment, the co-suspension composition as described herein includes: a suspension medium comprising a pharmaceutically acceptable HFA-based propellant; a plurality of particles of the active substance containing formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in a suspension medium at a concentration sufficient to provide a delivered dose of formoterol from about 0.5 μg to about 10 μg per actuation of the inhaler with a measured dose; and a plurality of respirable suspending particles containing perforated microstructures, as described herein, having a volume average optical diameter of from about 1.5 microns to about 10 microns, where the perforated microstructures are associated with a plurality of particles of the active substance to form a co-suspension. In one such embodiment, the formoterol active substance particles are formed from crystalline formoterol material. In another such embodiment, the ratio of the total mass of the suspending particles to the total particle weight of the active substance is selected from from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1. In another such embodiment, the formoterol active substance particles are formed from crystalline formoterol material and the ratio of the total mass of the suspending particles to the total mass of the active substance particles is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1. In another such embodiment, the formoterol active substance particles are formed from crystalline formoterol material, at least 90% of the formoterol active substance particles by volume exhibit an optical diameter of less than 7 μm, and the ratio of the total weight of the suspending particles to the total particle weight of the active substance is selected from from about 3 : 1 to about 15: 1; and from about 2: 1 to 8: 1.

In one embodiment, the co-suspension composition as described herein includes: a suspension medium comprising a pharmaceutically acceptable HFA-based propellant; a plurality of particles of the active substance containing formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in a suspension medium in a concentration sufficient to provide a delivered dose of formoterol from about 2 μg to about 10 μg per actuation of a metered-dose inhaler dose; and a plurality of respirable suspending particles containing perforated microstructures, as described herein, having a volume average optical diameter of from about 1.5 microns to about 10 microns, where the perforated microstructures are associated with a plurality of particles of the active substance to form a co-suspension. In one such embodiment, the formoterol active substance particles are formed from crystalline formoterol material. In another such embodiment, the ratio of the total mass of the suspending particles to the total particle weight of the active substance is selected from from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1. In another such embodiment, the formoterol active substance particles are formed from crystalline formoterol material and the ratio of the total mass of the suspending particles to the total mass of the active substance particles is selected from from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1. In another such embodiment, the formoterol active substance particles are formed from crystalline formoterol material, at least 90% of the formoterol active substance particles by volume exhibit an optical diameter of less than 7 μm, and the ratio of the total weight of the suspending particles to the total particle weight of the active substance is selected from from about 3 : 1 to about 15: 1; and from about 2: 1 to 8: 1.

In another embodiment, the co-suspension composition as described herein includes: a suspension medium comprising a pharmaceutically acceptable HFA-based propellant; a plurality of particles of the active substance containing salmeterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, suspended in a suspension medium in a concentration sufficient to provide a delivered dose of salmeterol from about 8 μg to about 40 μg per actuation of the metered-dose inhaler dose; and a plurality of respirable suspending particles containing perforated microstructures, as described herein, having a volume average optical diameter of from about 1.5 microns to about 10 microns, where the perforated microstructures are associated with a plurality of particles of the active substance to form a co-suspension. In one such embodiment, salmeterol active substance particles are formed from crystalline salmeterol material. In another such embodiment, the ratio of the total mass of the suspending particles to the total particle weight of the active substance is selected from from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1. In another such embodiment, the salmeterol active substance particles are formed from crystalline salmeterol material and the ratio of the total mass of the suspending particles to the total mass of the active substance particles is selected from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1. In another such embodiment, the particles of the active substance of salmeterol are formed from the material of crystalline salmeterol, at least 90% of the particles of the active substance of salmeterol exhibit an optical diameter of less than 7 μm in volume, and the ratio of the total mass of the suspending particles to the total particle mass of the active substance is selected from from about 3 : 1 to about 15: 1; and from about 2: 1 to 8: 1.

Metered dose inhalation systems

As described with reference to the methods provided herein, the compositions described herein can be used in an MDI system. MDIs are designed to deliver a specific amount of an aerosolized drug. In one embodiment, the MDI system includes a container filled with a liquid-phase composition under pressure placed in a drive device made with a mouthpiece. An MDI system may include formulations described herein that include a suspension medium, glycopyrrolate, and at least one type of suspending particles. The container used in the MDI may have any suitable configuration, and in one illustrative embodiment, the container may have a volume in the range of from about 5 ml to about 25 ml, such as a container having a volume of 19 ml. After shaking the device, the mouthpiece is placed in the patient’s oral cavity between the lips and teeth. The patient, as a rule, exhales deeply to empty the lungs, and then takes a slow, deep breath while putting the cassette in action.

Inside the illustrative cartridge there is a metering valve including a metering chamber capable of containing a specific volume of formulation (e.g., 63 μl or any other suitable volume available in commercially available metering valves) that is released into the expansion chamber at the far end of the valve stem when actuated. The drive device supports the container and may also include an opening with a nozzle of the drive device to accommodate the stem of the metering valve. When activated, a specific volume of the composition passes into the expansion chamber, leaves the nozzle of the drive device and is converted into aerosol at high speed, which is pulled into the patient's lungs.

IV. Ways

Methods for the manufacture of pharmaceutical compositions for respiratory delivery of the active substances LAMA and LAMA are described herein. In particular embodiments, such methods involve the steps of providing a suspension medium, active substance particles selected from active substance particles containing LAMA and active substance particles containing LABA, and one or more types of suspending particles, as described herein, and combining such components with the formation of a composition where the particles of the active substance are associated with suspending particles and are located together with the suspending particles in a suspension medium, so that a suspension was developed. In one such embodiment, the association of the glycopyrrolate particles and the suspending particles is such that they do not separate due to their buoyancy forces in the propellant. As will be understood, the method may include providing two or more types of suspending particles in combination with particles of the active substance. In another embodiment, the method may include providing two or more types of particles of the active substance and combining two or more types of particles of the active substance with one or more types of suspending particles so as to obtain a slurry. In certain embodiments, the particles of the active substance essentially consist of the active substance LAMA or LABA, as described herein.

In specific embodiments of the methods for providing a stabilized LAMA or LABA active substance composition for pulmonary delivery, the present disclosure relates to methods for inhibiting a solution-mediated conversion of an active substance in a pharmaceutical composition for pulmonary delivery. In one embodiment, a suspension medium is prepared as described herein, such as a suspension medium formed by an HFA propellant. Suspending particles are also prepared or prepared as described herein. Particles of the active substance are also obtained, and the suspension medium, the suspending particles and the particles of the active substance are combined to form a slurry, where the particles of the active substance are associated with the suspending particles and are together with the suspending particles in a continuous phase formed by the suspension medium. Compared with the active substance contained in the same suspension medium in the absence of suspending particles, it was found that the co-suspensions according to the present description exhibit higher resistance to solution-mediated transformation and irreversible aggregation of crystals, and thus can lead to increased stability and uniformity dosage.

In further embodiments, methods for forming stabilized LAMA or LABA active substance compositions for pulmonary delivery include preserving the FPF and / or FPD composition throughout the emptying of the MDI tank. In specific embodiments of the methods for preserving the FPF and / or FPD provided by the pharmaceutical composition for pulmonary delivery, there is provided an respirable co-suspension, as described herein, which is capable of keeping the FPD and / or FPF within ± 20%, ± 10%, or even ± 5% of the initial FPD and / or FPF, respectively, during the emptying of the MDI capacity. Such characteristics can be ensured even after the co-suspension is subjected to accelerated degradation. In one embodiment, a suspension medium is prepared as described herein, such as a suspension medium formed by an HFA propellant. Suspending particles are also prepared or prepared as described herein. Particles of the active substance are also obtained, and the suspension medium, suspending particles and particles of the active substance are combined to form a co-suspension, where the particles of the active substance are associated with the suspending particles and are together with the suspending particles in the suspension medium. Even after exposure to such compositions of one or more acts of cyclic temperature change, the slurry retains FPD or FPF within ± 20%, ± 10%, or even ± 5% of the corresponding values measured before exposure to the composition of one or more acts of cyclic temperature change.

Methods of making MDI for pulmonary delivery of the active substance LAMA or LABA are described. A method of manufacturing an MDI may include filling a container, as described herein, with particles of the active substance and suspending particles. The valve of the drive unit can be attached to the end of the container and the container sealed. The valve of the actuator device can be adapted to distribute a measured amount of the glycopyrrolate pharmaceutical composition to actuation. The container may be filled with a pharmaceutically acceptable suspension medium, such as a propellant, as described herein. As a result of this, the particles of the active substance and the suspending particles form a stable co-suspension in a suspension medium.

In methods involving pulmonary delivery of the active substance LAMA or LABA using the compositions described herein, the compositions can be delivered using MDI. Thus, in specific embodiments of such methods, an MDI is prepared, filled with the composition described herein, and the active substance LAMA or LABA is administered to the patient via pulmonary delivery by actuating the MDI. For example, in one embodiment, after shaking the MDI device, the mouthpiece is placed in the patient’s oral cavity between the lips and teeth. The patient usually exhales deeply to empty the lungs, and then takes a slow, deep breath while driving the MDI cassette. When activated, a specific volume of the composition passes into the expansion chamber, leaves the nozzle of the drive device and is converted into aerosol at high speed, which is pulled into the patient's lungs. In one embodiment, the dose of the active substance delivered during the emptying of the MDI tank is not more than 30% higher than the average delivered dose and not less than 30% less than the average delivered dose. Thus, methods are also provided for achieving the desired DDU of glycopyrrolate delivered from MDI. In such embodiments, a method may include achieving a DDU for glycopyrrolate delivered from an MDI selected, for example, from DDU ± 30% or better, DDU ± 25% or better, and DDU ± 20% or better.

Provided herein are methods for treating patients suffering from an inflammatory or obstructive disease or lung condition. In specific embodiments, such methods include pulmonary delivery of a therapeutically effective amount of a pharmaceutical composition described herein, and, in some such embodiments, pulmonary administration of a pharmaceutical composition is accomplished by delivering the composition using MDI. The disease or condition to be treated can be selected from any inflammatory or obstructive disease or condition of the lungs that responds to the administration of a LAMA or LABA agent. In certain embodiments, the pharmaceutical compositions described herein can be used to treat a disease or disorder selected from asthma, COPD, exacerbation of airway hyperresponsiveness due to other drug therapy, allergic rhinitis, sinusitis, constriction of the blood vessels of the lungs, inflammation, allergies, difficulty respiration, respiratory distress syndrome, pulmonary hypertension, narrowing of the vessels of the lungs and any other respiratory disease, condition, symptom, genotype or a phenotype that may respond to the administration of LAMA or LABA, alone or in combination with other methods of therapy. In certain embodiments, the compositions, systems, and methods described herein can be used to treat inflammation and obstruction of the lungs associated with cystic fibrosis.

In addition, the pharmaceutical compositions of the present description, delivered from MDI, provide the desired pharmacodynamic (PD) characteristics. In specific embodiments, pulmonary delivery of the pharmaceutical compositions described herein leads to a rapid significant increase in lung capacity, which can be characterized by an increase in forced expiratory volume in one second (FEV ₁ ) in a patient. For example, in specific embodiments, methods are provided for achieving a clinically significant increase in FEV ₁ , where such methods include providing a co-suspension composition containing the active substance LABA or LAMA, as described herein, and administering such a composition to a patient having pneumonia or lung obstruction through MDI. For the purposes of the present description, a clinically significant increase in FEV ₁ is an increase of 100 ml or more, and in certain embodiments of the methods described herein, administration of the compositions of the present description to a patient results in a clinically significant increase in FEV ₁ within 1 hour or less . In other such embodiments, methods of administering the composition, as described herein, to a patient via MDI result in a clinically significant increase in FEV ₁ within 0.5 hours or less. Compositions provided and delivered in such embodiments may include a composition comprising a LAMA active substance or a composition comprising a LABA active substance as described herein.

In further embodiments, methods are provided for achieving an increase in FEV _{1 of} more than 100 ml. For example, in certain embodiments, the methods described herein include methods for providing an increase in FEV _{1 of} 150 ml or more within a time period selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less. In other embodiments, the methods described herein include methods for achieving an increase in FEV _{1 of} 200 ml or more within a time period selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less, and 2 hours or less. In certain such embodiments, a composition comprising the active substance LABA or LAMA as described herein is provided and is administered to a patient having pneumonia or obstruction of the lung using MDI.

In further embodiments, methods are provided for achieving and maintaining a clinically significant increase in FEV ₁ . In specific embodiments, when administering a single dose of the LABA or LAMA active substance formulated as a composition as described herein to a patient using MDI, a clinically significant increase in FEV _{1 is} achieved over a period of time selected from 0.5 hours or less, 1 hours or less, and 1.5 hours or less, and a clinically significant increase in FEV ₁ persists for up to 12 hours or more. In certain such embodiments, the increase in FEV ₁ can be selected from an increase of 150 ml or more, 200 ml or more and 250 ml or more, and the increase in FEV ₁ remains clinically significant for a period of time selected from up to 4 hours, up to up to 6 hours, up to 8 hours, up to 10 hours and up to 12 hours, or more. In certain such embodiments, there is provided a composition comprising the active substance LABA or LAMA, as described herein, and is administered to a patient having pneumonia or obstruction of the lungs using MDI.

The compositions, systems and methods described herein are suitable not only to achieve the desired pharmacodynamic characteristics in short periods of time, but can also provide such results in a high percentage of patients. For example, methods provided herein are for achieving an increase in FEV _{1 of} 10% or more in 50% or more of patients having pneumonia or obstruction. For example, in specific embodiments, methods for achieving a 10% or more increase in FEV ₁ in a patient include providing a co-suspension composition containing the active substance LABA or LAMA as described herein, and administering such a composition via MDI to a patient having pneumonia or obstruction. In certain such embodiments, administering the composition will increase FEV ₁ by 10% or more within a time period selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours at 50% or more patients. In other such embodiments, administration of the composition will increase FEV ₁ by 10% or more within a time period 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 patients. In other such embodiments, administration of the composition will increase FEV ₁ by 10% or more within a time period selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours or less 70% or more patients. In other such embodiments, administering the composition will increase FEV ₁ by 10% or more within a time period selected from 0.5 hours or less, 1 hour or less, 1.5 hours or less, and 2 hours or hours at 80 % or more patients.

In specific embodiments, the methods described herein facilitate the treatment of patients having pneumonia or obstruction of the lungs, where such methods include providing a co-suspension composition containing the active substance LABA or LAMA, as described herein, and administering such a composition to a patient having inflammation or obstruction of the lungs through MDI, and lead to a high proportion of those patients who experience either an increase in FEV ₁ from the baseline of at least 200 ml or an increase in FEV _{1 of} 12% and more than baseline in combination with a total increase of FEV ₁ of at least 150 ml. In certain such embodiments, the administration of the composition results in either an increase in FEV ₁ from the baseline of at least 200 ml or an increase in FEV ₁ by 12% or more from the baseline in combination with a total increase in FEV ₁ of at least 150 ml within a time period selected from 1 hour or less, 1.5 hours or less, 2 hours or less, and 2.5 hours or less in 50% or more patients. In other such embodiments, administration of the composition results in either an increase in FEV ₁ from the baseline of at least 200 ml or an increase in FEV ₁ by 12% or more from the baseline in combination with a total increase in FEV ₁ of at least 150 ml within a time period selected from 1 hour or less, 1.5 hours or less, 2 hours or less, and 2.5 hours or less in 60% or more patients. In other such embodiments, administration of the composition results in either an increase in FEV ₁ from the baseline of at least 200 ml or an increase in FEV ₁ by 12% or more from the baseline in combination with a total increase in FEV ₁ of at least 150 ml within a time period selected from 1.5 hours or less, 2 hours or less, 2.5 hours or less, and 3 hours or less in 70% or more patients. In other such embodiments, the administration of the composition results in either an increase in FEV ₁ from the baseline of at least ha 200 ml, or an increase in FEV ₁ by 12% or more from the baseline in combination with a total increase in FEV ₁ of at least 150 ml per within a time period selected from 1.5 hours or less, 2 hours or less, 2.5 hours or less and 3 hours or less in 80% or more patients.

In some embodiments, the pharmaceutical compositions provided herein from MDI provide an increase in lung capacity, which can be characterized by improving inspiratory capacity (IC), which is defined as the maximum volume of gas that can enter the lungs when fully inhaled after normal exhalation. For example, in specific embodiments, methods are provided for achieving a clinically significant increase in IC, where such methods include providing a co-suspension composition containing the active substance LABA or LAMA, as described herein, and administering such a composition to a patient having pneumonia or obstruction of the lung using MDI . For the purposes of the present description, a clinically significant increase in IC is any increase of 70 ml or more, and in certain embodiments of the methods described herein, administering the compositions of the present description to a patient results in a clinically significant increase in IC within 2 hours or less. In other such embodiments, methods of administering a composition as described herein to a patient using MDI result in a clinically significant increase in IC within 1 hour or less. In other such embodiments, administering the compositions of the present disclosure to a patient results in an increase in IC of 100 ml or more within a time period selected from 1 hour or less and 2 hours or less. In other such embodiments, administering the compositions of the present disclosure to a patient results in an increase in IC of 150 ml or more over a period of time selected from 1 hour or less and 2 hours or less. In the following such embodiments, the administration of the compositions of the present description results in an increase in IC of 300 ml or more within a time period selected from 1 hour or less and 2 hours or less. Compositions provided and delivered in such embodiments may include a composition comprising a LAMA active substance, or a composition comprising a LABA active substance, as described herein.

In specific embodiments of the methods described herein, provided compositions comprise an active LAMA. In such embodiments, the LAMA active substance may be selected, for example, from glycopyrrolate, dexypyrronium, tiotropium, trospium, aklidinium and darotropy, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In specific embodiments of the methods described herein, the composition is a cosuspension composition as described herein, which includes glycopyrrolate or any pharmaceutically acceptable salt, ester, isomer or solvate thereof. In other specific embodiments of the methods described herein, the composition is a cosuspension composition as described herein that includes tiotropium or any pharmaceutically acceptable salt, ester, isomer or solvate thereof. When glycopyrrolate or tiotropium is selected as the active substance for use in compositions manufactured as part of the methods described herein, the amount of glycopyrrolate or tiotropium included in the composition may be selected, for example, from amounts specifically described with respect to pharmaceutical compositions described in this document.

In the following embodiments of the methods described herein, the provided compositions comprise the active substance LABA. In such embodiments, the LABA active substance can be selected, for example, from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol, milveterol, indacaterol and saligenin or indole-containing β ₂ agonists and β ₂ agonists derived from adamantyl and their any pharmaceutically acceptable salts, esters, isomers or solvates thereof. In specific embodiments of the methods described herein, the composition is a cosuspension composition as described herein that includes formoterol or any pharmaceutically acceptable salt, ester, isomer or solvate thereof. In other specific embodiments of the methods described herein, the composition is a cosuspension composition as described herein that includes salmeterol or any pharmaceutically acceptable salt, ester, isomer or solvate thereof. When formoterol or salmeterol is selected as the active substance for use in the compositions manufactured as part of the methods described herein, the amount of formoterol or salmeterol included in the composition can be selected, for example, from amounts specifically described in relation to pharmaceutical compositions described in this document.

The compositions, methods and systems described herein provide the desired dose effectiveness and dose effect for LAMA or LABA active substances formulated for pulmonary delivery. For example, pulmonary glycopyrrolate delivery for the treatment of conditions such as COPD has previously been proposed or described in Schroeckenstein et al., J. Allergy Clin. Immunol., 1988; 82 (1): 115-119, Leckie et al., Exp. Opin. Invest. Drugs, 2000; 9 (1): 3-23, Skorodin, Arch. Intern. Med., 1993; 153: 814-828, Walker et al., Chest, 1987; 91 (1): 49-51, and international patent publication WO / 1997/039758. These references describe the minimum effective dose for glycopyrrolate 200 μg - 1000 μg. Such dosage requirements are consistent with the clinical results for humans described by Bannister et al. U.S. Pat. 7229607, where a dose of glycopyrrolate of 480 μg was administered to individuals. As described in Example 6 herein, glycopyrrolate formulations prepared as described herein and delivered to humans using MDI provided a rapid onset of action and a clinically significant improvement in FEV ₁ and IC in accordance with the methods described herein, even when delivered significantly lower doses of glycopyrrolate (the largest single dose delivered in the study was 144 mcg).

Singh et al. [D. Singh, PA Corris and SD Snape. "NVA237, a once-daily inhaled antimuscarinic, provides 24-hour bronchodilator efficacy in patients with moderate to severe COPD" Poster presented at the American Thoracic Society International Conference, San Diego, California, May 19-24, 2006] described clinical work where glycopyrrolate was administered to humans via pulmonary delivery at doses of 20 mcg, 125 mcg, 250 mcg and 400 mcg. Although such doses were in the range below the 200 μg threshold previously described, as also described in detail in Example 6, glycopyrrolate formulations prepared and delivered as described herein still provided relatively increased dose efficiencies. For example, the AUC changes for FEV ₁ provided by the glycopyrrolate co-suspensions as described and evaluated in the clinical trial described in Example 6 are compared with the AUC changes for FEV ₁ provided by the compositions according to Singh et al. figure 10. The dose of 18 μg glycopyrrolate from Example 6 provided a better response to the bronchodilator than the 20 μg dose described by Singh et al. and the 36 μg and 144 μg glycopyrrolate doses of Example 6, providing a comparable response to the bronchodilator with doses of 125 μg and 250 μg respectively described by Singh et al.

In specific embodiments, methods are provided for achieving the desired pharmacodynamic effects, where the methods include administering a co-suspension composition, as described herein, to a patient via a metered-dose inhaler, where the co-suspension includes particles of the active substance glycopyrrolate, as described herein, to a patient using an inhaler with measured dose, so that a delivered dose of not more than 150 μg of glycopyrrolate is administered to the patient. In one embodiment, a method is provided for achieving clinically significant FEV ₁ , wherein the method comprises administering a co-suspension, as described herein, containing particles of the active substance of glycopyrrolate, to a patient using a metered-dose inhaler, so that a delivered dose of not more than 150 μg of glycopyrrolate is administered to the patient . In one such embodiment, a delivered dose of not more than 100 μg of glycopyrrolate is administered to a patient, and in another embodiment, a delivered dose of not more than 80 μg of glycopyrrolate is administered to a patient. Even when doses of not more than 80 μg, not more than 100 μg of glycopyrrolate, or not more than 150 μg of glycopyrrolate are administered to a patient, in specific embodiments, a clinically significant increase in FEV _{1 is} achieved within 1 hour or less. In some such embodiments, a clinically significant increase in FEV _{1 is} achieved within 0.5 hours or less.

In further embodiments, methods are provided for achieving an increase in FEV _{1 of} more than 100 ml, where the methods include administering a co-suspension, as described herein, containing particles of the active substance glycopyrrolate, to a patient using a metered-dose inhaler, so that the delivered dose is not more than than 150 mcg of glycopyrrolate. For example, in certain embodiments, methods are provided for providing an increase in FEV _{1 of} 150 ml or more within a time period selected from 0.5 hours or less, 1 hour or less and 1.5 hours or less, where the methods include administering cosuspension, such as described herein, containing particles of the active substance of glycopyrrolate, to a patient using a metered dose inhaler, so that a delivered dose of glycopyrrolate of not more than 150 μg is administered to the patient. In other embodiments, the methods described herein include methods for providing an increase in FEV _{1 of} 200 ml or more within a time period selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less, and 2 hours or less, where the methods include administering a co-suspension, as described herein, containing particles of the active substance of glycopyrrolate, to the patient using a metered-dose inhaler, so that a delivered dose of glycopyrrolate of not more than 150 μg is administered to the patient.

In further embodiments, methods are provided for achieving and maintaining a clinically significant increase in FEV ₁ , where the methods include administering a co-suspension, as described herein, containing particles of the active substance glycopyrrolate, to a patient using a metered dose inhaler, so that the delivered dose is not more than 150 mcg glycopyrrolate. In certain such embodiments, upon administration of a single delivered dose of glycopyrrolate of more than 150 μg, a clinically significant increase in clinically FEV _{1 is} achieved over a period of time selected from 0.5 hours or less, 1 hour or less and 1.5 hours or less, and a clinically significant increase in FEV ₁ persists for up to 12 hours or more. For example, in specific embodiments, an increase in FEV ₁ can be selected from an increase of 150 ml or more, 200 ml or more and 250 ml or more, and an increase in FEV ₁ remains clinically significant for a period of time selected from up to 4 hours, up to up to 6 hours, up to 8 hours, up to 10 hours and up to 12 hours or more.

Also provided are methods for providing either an increase in FEV ₁ from the baseline of at least 200 ml, or an increase in FEV ₁ by 12% or more from the baseline in combination with a total increase in FEV ₁ of at least 150 ml, where the methods include administering cosuspension, as described herein, containing particles of the active substance of glycopyrrolate, to a patient using an inhaler with a metered dose of not more than 150 μg of glycopyrrolate. In certain such embodiments, administering a delivered dose of not more than 150 μg of glycopyrrolate from cosuspension, as described herein, using a metered dose inhaler results in either an increase in FEV ₁ from the baseline of at least 200 ml or an increase in FEV ₁ 12% or more of baseline in combination with a total increase of FEV ₁ of at least 150 ml within a time period selected from 1 hour or less, 1.5 hours or less, 2 hours or less, and 2.5 hours or less in 50% or more patients. In other such embodiments, administering a delivered dose of not more than 150 μg of glycopyrrolate from cosuspension, as described herein, through a metered dose inhaler, either leads to an increase in FEV ₁ from the baseline of at least 200 ml or an increase in FEV ₁ by 12% or more of the baseline combined with a total increase of FEV ₁ of at least 150 ml within a time period selected from 1 hour or less, 1.5 hours or less, 2 hours or less, and 2.5 hours or less than 60% or more patients. In other such embodiments, administering a delivered dose of not more than 150 μg of glycopyrrolate from cosuspension, as described herein, through a metered dose inhaler results in either an increase in FEV ₁ from the baseline of at least 200 ml or an increase in FEV ₁ by 12 % or more of the baseline in combination with a total increase of FEV ₁ of at least 150 ml within a time period selected from 1.5 hours or less, 2 hours or less, 2.5 hours or less, and 3 hours or less in 70% or more patients. In other such embodiments, the administration of a delivered dose of not more than 150 μg of glycopyrrolate from cosuspension, as described herein, through a metered-dose inhaler results in either an increase in FEV ₁ from the baseline of at least 200 ml or an increase in FEV ₁ 12% or more of baseline in combination with a total increase of FEV ₁ of at least 150 ml within a time period selected from 1.5 hours or less, 2 hours or less, 2.5 hours or less, and 3 hours or less in 80% or more patients.

Methods are provided for providing a clinically significant increase in IC, where the methods include administering a co-suspension, as described herein, containing particles of the active substance glycopyrrolate, to the patient via a metered-dose inhaler, so that a delivered dose of not more than 150 μg glycopyrrolate is administered to the patient. In certain such embodiments, administering a delivered dose of not more than 150 μg glycopyrrolate from cosuspension, as described herein, through a metered dose inhaler results in a clinically significant increase in IC within 1 hour or less. In other such embodiments, the administration of a delivered dose of not more than 150 μg of glycopyrrolate from cosuspension, as described herein, through a metered dose inhaler results in an increase in IC of 100 ml or more over a period of time selected from 1 hour or less and 2 hours or less. In other such embodiments, administering a delivered dose of not more than 150 μg of glycopyrrolate from cosuspension, as described herein, using a metered dose inhaler results in an increase in IC of 150 ml or more over a period of time selected from 1 hour or less and 2 hours or less. In further such embodiments, administering a delivered dose of not more than 150 μg glycopyrrolate from cosuspension, as described herein, using a metered dose inhaler results in an increase in IC of 300 ml or more over a period of time selected from 1 hour or less and 2 hours or less.

The specific examples included in this document are for illustrative purposes only and should not be construed as limiting this description. Moreover, the compositions, systems and methods described herein are described with reference to their specific options for implementation, and many details are indicated for purposes of illustration, specialists in this field it is clear that additional embodiments of the invention are possible, and that certain details described in herein may vary without departing from the grounded principles of the invention. Any active substances and reagents used in the examples below are either commercially available or can be obtained by specialists in the field of organic synthesis according to standard methods described in the literature. The full contents of all publications, patents, and patent applications referred to in this document are incorporated herein by reference.

Example 1

Particles of the active substance formed from glycopyrrolate (pyrrolidinium, 3 - ((cyclopentylhydroxyphenylacetyl) oxy) -1,1-dimethyl bromide) were obtained by micronization of glycopyrrolate using a jet mill. The particle size distribution of micronized glycopyrrolate (GP) was determined by laser diffraction. 50% by volume of micronized particles had an optical diameter of less than 2.1 microns, 90% by volume were less than 5 microns.

Suspending particles were prepared as follows: 500 ml of an emulsion of fluorocarbon PFOB (ferrofluorotil bromide) in phospholipid-stabilized water was prepared. 18.7 g of phospholipid, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) and 1.3 g of calcium chloride were homogenized in 400 ml of hot water (75 ° C) using a high shear mixer. Slowly add 100 ml PFOB during homogenization. The resulting coarse emulsion was then further homogenized using a high pressure homogenizer (Model C3, Avestin, Ottawa, CA) at pressures up to 170 MPa for 5 treatment cycles.

The emulsion was dried by spray drying in nitrogen using the following spray drying conditions: inlet temperature 95 ° C, outlet temperature 72 ° C, emulsion feed rate 2.4 ml / min, total gas flow 525 l / min. The size distribution of the suspending particles was determined by laser diffraction. 50% by volume of the suspending particles were less than 2.9 μm, the geometric standard deviation of the distribution was 1.8.

Metered dose inhalers were made by weighing a given mass of micronized GP particles and suspending particles into aluminum containers coated with a fluorinated ethylene polymer (FEP) (Presspart, Blackburn, UK) with a volume of 19 ml. The target masses and the target delivery dose, assuming a 20% deposit in the drive unit, are given in table 1 for five different configurations (configurations 1A to 1C corresponding to different suspensions of GP particles and suspending particles; configuration 1D corresponding to GP particles separately; configuration 1E, corresponding to the suspending particles separately). The containers were sealed using 63 μl valves (# BK 357, Bespak, King's Lynn, UK) and filled with 12.4 g of HFA 134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst, UK) through the valve stem. After injection of the propellant, the containers were sonicated for 15 seconds and shaken on a hand-type shaker for 30 minutes. The tanks were equipped with polypropylene drive devices with a 0.3 mm hole (# BK 636, Bespak, King's Lynn, UK). Additional inhalers for visual examination of the quality of the suspension were obtained using glass vials.

Table 1
Results for glycopyrrolate co-suspensions according to Example 1 Configuration id GP mg / capacity Suspending Particles (mg / capacity) Preset Delivery Dose (mcg) Delivered Dose mcg FPF (%) MMAD (μm) 1A 3.4 61 16.5 17.8 41.3 3,7 1B 4.1 61 twenty 19,4 42.0 3.9 1C 4.1 fifteen twenty 19,2 42.7 3.2 1D 4.1 0 twenty 11.1-15.3 27.0 3.3 1E 0 61 - - 53.6 * 3.2 * Based on DSPC analysis.

Aerosol performance was evaluated shortly after manufacture according to USP <601> (United States Pharmacopeia Monograph 601). To determine the particle size distribution, the Next Generation Impactor (NGI) was used, operating at a flow rate of 30 l / min. Sample containers were placed in the drive unit with two dump actuations and two additional dump preliminary actuations. The results of five actuations were combined in NGI with an attached USP nozzle. The valve, actuator, nozzle, NGI cups, plates, and filter were rinsed using a volume distributed solvent. Sample solutions were analyzed using a chromatographic method specific for the drug. The fraction of fine particles was determined using the sum for cascades from 3 to the filter. Testing the uniformity of the delivered dose during use was performed using a dose uniformity sampling device as described in USP <601>. Inhalers were placed and filled as described above. Samples of two actuations were collected and analyzed at the beginning, in the middle and at the end of application.

A visual study of the co-suspended configurations (1A, 1B, 1C) showed no precipitation of drug crystals. The suspension slowly precipitated in the form of flakes and formed a homogeneous single exfoliated layer, similar to the configuration for comparison 1E, which included suspendida particles suspended separately. On the contrary, micronized particles of GP separately (configuration 1D) quickly formed a precipitate in the form of flakes and settled. Configuration 1B showed no signs of separation of GP particles from the suspending particles even after centrifugation at 35 g for 20 minutes. The same result was observed (i.e., lack of separation of GP particles) by centrifugation at up to 200 g. Configuration 1C (low concentration of suspending particles) showed a small amount of GP crystals precipitated after centrifugation at 35 g for 20 minutes.

While the co-suspended configurations reached a delivered dose within 10% of the target, the GP particles suspended separately showed significantly higher variability of the delivered dose in a range well below the target. The fine particle fraction relative to the 1D configuration was better than more than 50%. MMAD cosuspended configurations were acceptable and depended on the suspension concentration of the suspending particles. The uniformity of delivered dose when tested was tested for configurations 1B and 1C. All individual delivered doses were within ± 20% of the mean. The results showed that drug crystals forming GP particles were associated with suspending particles, cosuspension formed, and aerosol characteristics in cosuspension were mainly determined by suspending particles.

The association between GP crystals and suspending particles was strong enough to overcome buoyancy forces, since it was found that GP crystals did not separate from perforated microstructures and crystal settling was inhibited.

Example 2

Glycopyrrolate (GP) particles were formed by micronization using a jet mill. Suspending particles were made as described in Example 1. The particle size distribution of the micronized GP was determined by laser diffraction. 50% by volume of micronized particles had an optical diameter of less than 1.7 microns, 90% by volume had an optical diameter of less than 4.1 microns. Five different batches of metered-dose inhalers were made. For configurations 2A, 2B, and 2C, the total concentration of DSPC, CaCl _2, and GP in the raw material was 40 mg / ml; for 2D and 2E, this concentration was two times higher.

Metered dose inhalers were made by weighing the given masses of GP particles and suspending particles in a container as described in Example 1. No other excipients were used. The target weights were 4 mg / capacity for GP particles and 60 mg / capacity for suspending particles, which resulted in a suspending particle to GP particle ratio of 15 for the 2A and 2D configurations. The target weights were 5.1 mg / capacity for GP particles and 51 mg / capacity for suspending particles, which resulted in a suspending particle / GP particle ratio of 10 for configuration 2B. The target weights were 8 mg / capacity for GP particles and 60 mg / capacity for suspending particles, resulting in a suspending particle to GP particle ratio of 7.5 for the 2C and 2E configurations. The propellant and closure system of the container were as described in example 1.

GP crystals were placed in HFA 134a in a container under pressure and balanced for 3 weeks at room temperature to determine their solubility in the propellant. Samples were filtered under pressure at ambient temperature through filters with a pore width of 0.22 μm. The filtrate was evaporated and GP was dissolved in methanol and analyzed chromatographically. A solubility of 0.17 ± 0.07 μg / g was detected. Using this value, it was determined that 2.1 μg or 0.05% of GP dissolved in the propellant was present in the container. In previous articles, it has been described that microcrystalline material with measurable solubility in the propellant is not physically stable due to solution-mediated transformation [N. C. Miller, The Effects of Water in Inhalation Suspension Aerosol Formulations, PA Byron, Ed., Respiratory Drug Delivery, CRC Press, 1990, p 250], or that active substances with a solubility higher than 0.1 μg / g should be prepared with adjuvant to prevent solution-mediated conversion [P. Rogueda, Novel Hydrofluoroalkane Suspension Formulations for Respiratory Drug Delivery, Expert Opin. Drug DeNv. 2, 625-638, 2005].

Filled metered-dose inhalers were stored flap-down without an overwrap under two different conditions: 1) in a refrigerator at 5 ° C; and 2) at room temperature at 25 ° C / 60% RH. Tests of aerosol characteristics and uniformity of the delivered dose, as described in Example 1, were carried out at various points in time. The results, which are summarized in table 2, demonstrate a stable fraction of fine particles under cooling conditions and at room temperature.

table 2
Fine particle fraction configurations of example 2 # Storage FPF in% Initial 2 months 3 months 6 months 2A 5 ° C 49 51 52 - 25 ° C / 60% RH 48 51 - 2B 25 ° C / 60% RH fifty 46 49 48 2D 5 ° C 51 54 54 - 25 ° C / 60% RH 46 49 49

Configurations 2C and 2E were subjected to a temperature cycling test. The containers were subjected to alternating temperatures of -5 ° C and 40 ° C every 6 hours for a total duration of twelve weeks. The fine particle fraction was 53% for both configurations at the start of the study. After twelve weeks under cyclic conditions, the FPF did not change, i.e. was 55% for configuration 2C and 53% for configuration 2E.

The uniformity of the delivered dose during use was tested at time points 1, 2 and 6 months. All individual delivered doses were within ± 20% of the mean. Figures 1 and 2 show the aerosol particle size distribution as measured by NGI for configurations 2A and 2B, respectively. Also shown are the amounts of drug released from the drive unit and from the inlet (nozzle) and its mouthpiece adapter. The resulting masses are expressed as a percentage of the nominal dose. For configuration 2A, individual repetitions for aerodynamic particle size distribution are presented at 4, 8, and 12 weeks, and for configuration 2B, at 8, 12, and 24 weeks. Although there is a measurable fraction of suspended GP dissolved in the propellant, there is no evidence of coarsening of size distributions. Moreover, as these examples show, the aerosol characteristics of the suspension at acceptable ratios of suspending particles and GP are determined mainly by suspending particles.

Example 3

Several similar batches of suspending particles were obtained as described in Example 1. Suspending particles were combined with particles of glycopyrrolate (GP), micronized to various degrees, using two different types of jet mills with different grinding parameters. The optical diameter and particle size distribution of micronized GP was determined by laser diffraction. Table 3 shows the values of d ₅₀ and d ₉₀ for various batches of micronized material used. d ₅₀ and d ₉₀ denote the particle size at which the cumulative volume distribution using the device for determining the particle size reaches 50% and 90%, respectively.

Twelve different batches of metered-dose inhalers were prepared as described in Example 1. In all cases, the concentration in the suspension of GP particles in HFA 134a was in the range of 0.32-0.45 mg / ml and the concentration in the suspension of suspending particles was in the range of 5, 8-6.1 mg / ml. The configurations were considered similar enough to combine the data for the meta-analysis presented in this example.

Filled metered-dose inhalers were stored with the valve down without an overwrap under two different conditions: cooling at 5 ° C and controlled room temperature at 25 ° C / 60% RH. Tests of aerosol performance, as described in Example 1, were carried out at various points in time. The results did not show any statistically significant trend as a function of time for up to twelve weeks of storage. No differences were found between storage at room temperature and storage under cooling. Thus, the results for various load conditions and time points were combined to determine how the particle size distribution of the micronized material affects the aerosol characteristics.

Table 3 summarizes the results of MMAD in a meta-analysis. The first column describes six different configurations. The second column identifies how many individual batches were used to combine the data for the corresponding configuration. The third column shows the number of individual MMAD definitions used to calculate the average MMAD for the corresponding configuration. The fourth and fifth columns show d ₉₀ and d ₅₀ micronized material used for the manufacture of slurries. Results are sorted by d ₉₀ from coarse to thin. The last two columns represent the mean MMAD and standard deviation.

Table 3
Combined MMAD results for 12 glycopyrrolate co-suspensions, sorted by d ₉₀ micronized glycopyrrolate particles Party id number of parties Number of MMAD Measurements d ₉₀ (μm) d ₅₀ (μm) Medium MMAD (μm) SD 3A 3 21 5,0 1.8 4.0 0.28 3B 2 9 4.9 2.1 4.1 0.37 3C one 6 4.8 1.8 3.6 0.12 3D one four 4.3 1.7 3,5 0.22 3E 3 twenty 4.1 1,6 3,7 0.28 3F 2 10 3,5 1.7 3.6 0.10

These results demonstrate a weak dependence of MMAD on d ₉₀ micronized material. A similar analysis of d ₅₀ showed the absence of a statistically significant trend. It can be concluded that changes in the distribution of particles of micronized material (for example, different batches of micronized material or induced by solution-mediated transformations) led only to small differences in the size distribution in the aerosol discharged from the metered-dose inhaler.

Example 4

Micronized glycopyrrolate (GP) particles were formed and tested as described in Example 1. The optical particle diameter of the micronized GP was determined and 50% by volume of particles of micronized GP were less than 1.7 μm, 90% by volume were less than 3.8 μm.

Five batches of suspending particles were prepared as described in Example 1. The batches differed in concentration, C _F , and volume fraction of PFOB, V _PFOB , raw emulsion before spray drying, ranging from 20 mg / ml to 160 mg / ml and from 20% up to 40%, respectively. The various configurations are described in table 4.

Metered dose inhalers were prepared by weighing a predetermined mass of micronized GP particles and suspending particles into 15 ml coated glass vials. Target concentrations in suspensions and ratios of suspending particles and GP are shown in Table 4 for 26 different vials tested. The containers were sealed using 63 μl valves (Valois, Les Vaudreuil, France) and filled with 10 g or 12 g of HFA 134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst, UK) by means of overpressure through the valve stem . After injection of the propellant, the containers were sonicated for 15 seconds and shaken on a hand-type shaker for 30 minutes.

As described in Example 1, micronized GP particles made separately quickly formed a flocculent precipitate and settled. The glass vials in this example were left to precipitate for at least 24 hours without shaking, and then they were tested by visual examination to see if the crystalline particles of GP were completely suspended. For vials marked “yes” in Table 4, no GP particles were observed at the bottom of the vials, with the exception of a very small number of foreign particles in some vials. Accidental foreign particles were also visible in very low numbers in vials filled only with suspending particles. For vials labeled “partially,” the GP particle fraction was visible at the bottom of the vial.

Table 4
Observations of co-suspension for glycopyrrolate configurations with different ratios of suspending particles and glycopyrrolate particles C _F in mg / ml V _pfob (%) C _s (mg / ml) The ratio of suspending particles and glycopyrrolate particles Cosuspension # Suspending Particles 4A twenty 40 1.8 3.8 Partially twenty 40 7.2 fifteen Yes 4B 40 40 3.0 1.9 Partially 40 40 1.8 3.8 Partially 40 40 3.0 3.8 Yes 40 40 6.0 3.8 Yes 40 40 9.0 5,6 Yes

40 40 3.0 7.5 Yes 40 40 6.0 7.5 Yes 40 40 9.0 11.3 Yes 40 40 6.0 fifteen Yes 40 40 7.2 fifteen Yes 40 40 9.0 22.5 Yes 4C 80 twenty 3.0 1.9 Partially 80 twenty 3.0 3.8 Partially 80 twenty 6.0 3.8 Yes 80 twenty 9.0 5,6 Yes 80 twenty 3.0 7.5 Yes 80 twenty 6.0 7.5 Yes 80 twenty 9.0 11.3 Yes 80 twenty 6.0 fifteen Yes 80 twenty 9.0 22.5 Yes 4D 80 40 1.8 3.8 Partially 80 40 7.2 fifteen Yes 4E 160 40 1.8 3.8 Partially 160 40 7.2 fifteen Yes

Example 5

The glycopyrrolate (GP) particles were micronized using a jet mill and tested as described in Example 1. 50% by volume of micronized GP particles showed an optical diameter of less than 1.7 μm, 90% by volume showed an optical diameter of less than 4.4 μm.

Six batches of suspending particles were made by spray drying as described in Example 1. Configuration 5A was spray dried from the emulsion. Configuration 5B was made in a similar manner, but using dipalmitoylphosphatidylcholine (DPPC) instead of DSPC. Configuration 5C was spray dried from a solution in ethanol. For configurations 5D, 5E, and 5F, saccharides were spray dried from an aqueous solution. The spray drying parameters for all configurations are given in table 5a.

Table 5a
Suspension Particle Configurations Used in Example 5 # lots The composition of the powder (% wt./mass.) Composition of raw materials (% vol./about.) C _F (mg / ml) Spray Drying Options Feed rate (ml / min) T _inlet (° C) T _output (° C) Total gas flow (l / min) 5A 93.5% DSPC
6.5% CaCI ₂ 80% H ₂ O
20% PFOB 40 2,4 95 72 526 5B 92.9% DPPC
7.1% CaCl ₂ 70% H ₂ O
30% PFOB 60 2,4 95 67 525 5C 100% DSPC 95% Ethanol 5% PFOB one hundred 5 95 70 520 5D 100% Lactose 100% H ₂ O one hundred four 95 70 668 5E 100% trehalose 100% H ₂ O 10 2,4 one hundred 68 527 5F 100% trehalose 100% H ₂ O 89 four one hundred 71 670

Particle size distribution for suspending particles was determined by laser diffraction. The volumetric mean optical diameter of the VMD and the geometric standard deviation of the GSD for various configurations are shown in Table 5b.

Table 5b
Characteristics of the suspending particle configurations used in Example 5 # lots VMD (μm) GSD Separation Cosuspension Comment 5A 3.6 1.8 Exfoliation Yes No or few visible crystals at the bottom of the vials 5B 3.6 1.8 Exfoliation Yes 5C 1,2 1.9 Exfoliation Partially 5D 1.7 2,3 Precipitation Yes Causes precipitation of GP crystals with suspending particles 5E 0.9 1.7 Precipitation Yes 5F 1.7 2,4 Precipitation Yes

Electron micrographs of the suspending particles showed a different morphology, summarized in Figure 3. Particles that were spray dried from the emulsion, 5A and 5B, had high porosity and low density. DSPC particles dried by spray drying from a solution in ethanol, 5C, showed a significantly smaller particle size with appreciable porosity, indicating a high density. All saccharides formed smooth particles without noticeable porosity. The 5E configuration had the smallest particle size, as expected, due to their low concentration of feed.

Metered dose inhalers were prepared by weighing 4 mg of micronized GP particles and 60 mg of suspending particles into 15 ml coated glass vials. The containers were sealed with 63 μl valves (Valois, Les Vaudreuil, France) and filled with 9.5 ml of HFA 134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst, UK) using overpressure through the valve stem. After injection of the propellant, the containers were sonicated for 15 seconds and shaken on a hand-type shaker for 30 minutes. Additional inhalers with suspending particles only were made as controls for each configuration.

The suspending particles of Examples 5A, 5B and 5C have a true density lower than that of the propellant. They exfoliated and were tested for the presence of cosuspension, as described in Example 4. No GP particles were visible at the bottom of the vials for configurations 5A and 5B. The 5C configuration formed a partial slack suspension.

Saccharide particles settle because they have a higher true density than the propellant, however, all control vials for saccharide configurations showed a significantly higher settling rate than micronized particles alone. In configurations 5D, 5E, and 5F, the sedimentation rate was similar to the speed in control vials with suspending particles separately and was faster than that of micronized GP particles separately, which demonstrates the association of GP crystals with suspending particles. In these cases, co-suspension formed. Figure 4 shows an example of this behavior for a 5D configuration. A glass vial was observed one minute after shaking. The slurry has already settled, leaving a transparent layer of the propellant, while in the control containing the GP particles separately, most of the crystals were still suspended in the propellant.

Example 6

Pharmaceutical compositions as described herein were evaluated in a multicenter clinical trial. MDI devices containing the glycopyrrolate pharmaceutical composition prepared as described herein were provided.

The suspending particles used were obtained in a similar manner to that described in Example 1. The MDI was made using a drug addition container (DAV), first adding half the amount of suspending particles, then filling it with microcrystalline GP, and then adding the second half of the suspending particles to the top. Materials were added to the tank under controlled humidity conditions <10% RH. Then DAV was combined with a 4 L suspension tank and sprayed with HFA 134a propellant and then mixed. The temperature inside the vessel was maintained at 21-23 ° C throughout the entire production of the batch. After recirculation of the batch for 30 minutes, the containers were filled with suspension mixture through 50 μl EPDM valves. Then, sample containers were randomly selected for a general analysis of the container to verify the correct amounts in the composition. Then, a freshly prepared batch of cosuspension in MDI was isolated for one week, and then the initial characteristics of the product were analyzed.

The composition was made and the MDI devices were configured to provide a dose of 18 μg glycopyrrolate per actuation of the MDI.

The study was a four-period, six-dose randomized, double-blind, placebo-controlled, and active substance crossover study that evaluated a single administration of 4 increasing doses of mild to moderate glycopyrrolate in patients with mild to moderate COPD compared to placebo and open-administered tiotropium (18 μg with Spiriva Handihaler) as a control. Six injections in the study were 18, 36, 72, and 144 μg MDI administrations given in one, two, four, or eight 18 μg sequential actuations per MDI with glycopyrrolate, Handihaler with tiotropium a dose of 18 mcg and a placebo MDI that was identical to MDI with glycopyrrolate but without glycopyrrolate. Each patient was randomly assigned to one of six possible sequences, which included four of the injections in the study. Each sequence included two or three doses of MDI with glycopyrrolate, which were administered in increasing order to each patient. The administration from MDI with glycopyrrolate and the MDI with placebo were blind, and the administration of tiotropium was open. Thirty-three patients were included and their safety was analyzed; thirty patients were tested for efficacy. The maximum improvement of FEV ₁ relative to the baseline on the day of testing was evaluated (FEV ₁ represents the maximum volume of air exhaled during the first second of maximum effort after maximum inhalation), the time to onset of action, the time to maximum FEV ₁ , AUC _0-12 for FEV ₁ , AUC _0-24 for FEV ₁ , AUC _12-24 for FEV ₁ , minimum FEV ₁ after 12 and 24 hours, and similar analyzes of maximum expiratory flow rate (PEFR) and FVC, as well as maximum improvement in inspiratory capacity (IC) . Blood samples were collected before dosing and 2, 6, 20 minutes and 1, 2, 4, 8, 12, and 24 hours after dosing to determine the plasma concentrations used to calculate PK parameters. The ratios of clinical spirometry results (FEV ₁ ) and PK results for glycopyrrolate (AUC _0-12 and Cmax) were determined.

All doses from MDI with glycopyrrolate were safe and well tolerated, and profiles of mean plasma glycopyrrolate concentration at time-time were well characterized by the rapidly appearing maximum plasma concentrations, typically within 20 minutes. Plasma glycopyrrolate levels increased with increasing dose levels. The figure 5 shows the concentration of glycopyrrolate in serum (in PG / ml) compared with placebo over a period of 24 hours in the studied individuals.

MDI with glycopyrrolate showed a statistically significant and clinically significant better efficacy compared with placebo MDI (p <0.001 for all four doses of glycopyrrolate) with a clear dose-response relationship. The efficacy of MDI with 144 μg glycopyrrolate and 72 μg glycopyrrolate was similar to that of 18 μg tiotropium in terms of maximizing FEV ₁ improvement over time. With regard to improving the secondary results of FEV ₁ from baseline on the day of testing, including the minimum FEV ₁ after 12 hours, AUC _0-12 for FEV ₁ , AUC _0-24 for FEV ₁ , AUC _12-24 for FEV ₁ , and minimum FEV ₁ after 12 and 24 hours, all doses from MDI with glycopyrrolate showed clinically significant and statistical superiority compared to placebo MDI (p <0.049 for all four dose levels), with the exception of improving the minimum FEV ₁ 24 hours after administration from MDI with 36 μg glycopyrrolate (difference compared with placebo = 0.073 L; p = 0.059). Similarly to the clear dose-effect relationship observed to improve maximum FEV ₁ , dose ordering was also observed for all four estimated doses from MDI with glycopyrrolate for AUC _0-12 for FEV ₁ , AUC _0-24 for FEV ₁ , and AUC _12-24 for FEV ₁ .

It was shown that MDI with doses of 144 μg and 72 μg of glycopyrrolate is not statistically less effective than 18 μg tiotropium in terms of the maximum change in FEV ₁ , AUC _0-12 for FEV ₁ , and AUC _0-24 for FEV ₁ , with a priori the border of no less efficiency, equal to 100 ml. A dose of 144 μg glycopyrrolate was also no less effective than a dose of tiotropium in terms of minimum FEV ₁ after 12 hours and AUC _12-24 for FEV ₁ . Point estimates of most FEV ₁ parameters for doses of 72 and 144 μg were within ± 50 ml compared with tiotropium. As a rule, secondary results (time to effect, maximum and minimum FEV _, FVC, PEFR and maximum IC) confirmed the data of the primary results. MDI with glycopyrrolate showed a faster onset of action compared to 18 μg tiotropium, with an average time of up to ≥10% improvement in FEV ₁ 1 hour or less for all estimated doses from MDI with glycopyrrolate, compared with approximately 3 hours for 18 μg tiotropium.

The figure 6 presents a graph of the average change in FEV ₁ from the initial level (in liters) in the studied individuals over a period of 24 hours. The figure 7 presents the change in FEV ₁ from the initial level (in liters) for patients with different dosage levels of glycopyrrolate compared with the results obtained for tiotropium. Specifically, FIG. 7 compares the peak change from baseline compared to the placebo value for various glycopyrrolate concentrations and the area under the curve over a period of 12 hours and 24 hours. Figure 8 shows the proportion of patients who experienced either 1) an increase in FEV ₁ from the baseline of at least 200 ml or 2) an increase in FEV ₁ by 12% or more from the baseline in combination with a total increase in FEV ₁ of at least 150 ml or more. The figure 9 shows the maximum improvement in IC in patients who were administered various doses of glycopyrrolate, as well as the maximum improvement in IC for patients who were administered tiotropium. Figure 10 shows the cumulative change in FEV ₁ over a period of 24 hours in patients who were injected with glycopyrrolate compared to the results obtained in another clinical trial, where NVA237 (powder composition of glycopyrrolate) was administered in various doses by Singh et al. (D. Singh, PA Corris and SD Snape. "NVA237, a once-daily inhaled antimuscarinic, provides 24-hour bronchodilator efficacy in patients with moderate to-severe COPD" Poster presented at the American Thoracic Society International Conference, San Diego, California , May 19-24, 2006).

Example 7

Glycopyrrolate (GP) was micronized using a jet mill to a volume average optical diameter (d ₅₀ ) of 1.4 μm with a 90% cumulative distribution (d ₉₀ ) having a volume optical diameter of less than 3.0 μm. Suspending particles were made in the same way as described in Example 1. MDI containers were made using Presspart FEP coated containers to provide metered dose products of 5.5 μg GP / actuation and 44 μg GP / actuation, which correlated with the delivered at a dose of approximately 4.5 μg GP / actuation and 36 μg GP / actuation from 50 μl of a volume-measuring chamber of commercially available Bespak valves. The compositions contained 6 mg / ml of suspending particles. MDI containers were made using a standard pressure filling process, where drug and suspending particles were mixed with HFA 134a in a suspension container and filled in an inhaler container using a commercially available filling head.

After manufacture, each batch was tested for uniformity of delivered dose over the course of being in the container and distributing the aerodynamic particle size using a Next Generation Impactor. The particle size distribution measured by NGI is shown in FIGS. 5 and 6. Also shown are the quantities of drug released from the valve stem and the actuator, and from the inlet (nozzle) and its mouthpiece adapter. The released masses are expressed as a percentage of the nominal dose. The fine particle fraction remained unchanged for 168 cycles, which illustrates the stability of the GP co-suspensions described herein over the dose range of GP. The delivered dose over the life of the MDI containers is shown in Figures 13 and 14. No change was observed in the delivered dose, first to the middle of the container, and a ~ 10% increase was observed first to the end of the container. The change from the middle to the end is expected, based on the loss of the propellant on evaporation as the tank is empty. The compositions described in this example demonstrate the desired uniformity of the delivered dose in MDI for doses already 4.5 micrograms per actuation.

In addition, containers from each batch were subjected to stability studies under cyclic temperature changes. The containers were subjected to alternating temperatures of -5 ° C and 40 ° C every 6 hours for a total duration of 84 cycles (3 weeks) and 168 cycles (6 weeks). After 184 cycles,% FPF (after the actuator) did not differ significantly from the original. A summary of the results for the stability of the fraction of fine particles is presented in table 6.

Table 6
Stability under cyclic temperature variation of the fraction of fine particles of crystalline GP, cuspensioned with suspending particles in two doses in MDI,
containing HFA 134a Time 4.5 μg per actuation (% FPF after drive unit) 36 mcg per actuation
(% FPF after drive unit) Source 60.9 57.4 3 weeks
(84 cycles) 61.9 58.0 6 weeks
(168 cycles) 60.6 59.0

The delivered dose over the life of the MDI containers is shown in FIGS. 7 and 8. No change was observed in the delivered dose, first to the middle of the container, and a ~ 10% increase was observed first to the end of the container. The change from the middle to the end is expected, based on the loss of the propellant on evaporation as the tank is empty. Figures 7 and 8 demonstrate the desired uniformity of the delivered dose in MDI for doses already 4.5 μg per actuation.

Example 8

MDI containers were made to contain a suspension concentration of 6 mg / ml and provide a metered dose of 36 μg / actuation with a valve volume of 50 μl according to Example 6. The micronized GP had d ₅₀ and d _{90 of} 1.6 μm and 4.1 μm, respectively, and suspending particles were made similarly to the method described in example 1. The containers were placed for stability studies without protective packaging at 25 ° C / 60% RH and stored for 12 months.

The aerodynamic particle size distribution was determined using a Next Generation Impactor after 2 weeks, 1, 2, 3, 6, or 12 months. The fraction of fine particles as a percentage of GP after the drive unit, at initial sampling, was 50.2%. No significant changes were detected in the fraction of fine particles at any time during 12 months, and after 12 months the FPF was 47.7%. The figure 15 presents an image of the complete distribution of the aerodynamic particle size for each of the time points, demonstrating the desired constancy upon delivery in aerosol. Summarized data for the fraction of fine particles are presented in table 7.

Table 7
The stability of the fine particles fraction of crystalline GP co-suspended with suspending particles in MDI containing HFA 134a at 25 ° C and 60% RH without protective wrap Moment of time % FPF (after drive unit) Source 50,2 2 weeks 46.1 1 month 42.0 2 months 46.0 3 months 48.9 6 months 47.7 12 months 47.7

Example 9

MDI containers were made to contain suspending particles at a concentration of 6 mg / ml and provide a metered dose of 36 μg / actuation as described in Example 7. These containers were packed in a heat-insulating aluminum foil wrap containing a desiccant and subjected to cyclic temperature changes for 6 weeks (6 hours at -5 ° C and 6 hours at 40 ° C). The uniformity of the delivered dose during use was tested at time points of 0, 2, 4, and 6 weeks. The average delivered glycopyrrolate dose of each batch each time period was within ± 15% of the average value, with one exception, as shown in Figure 16. The aerodynamic particle size distribution measured using NGI remained unchanged after 168 cycles of temperature change, as shown in the figure 17.

Example 10

MDI containers were made to contain suspending particles at a concentration of 6 mg / ml and provide a metered dose of 24 μg / actuation, as described in Example 7. These containers were stored for six weeks at 50 ° C. at ambient humidity. Another batch was stored for 8 weeks at 40 ° C and 75% relative humidity. Another batch was stored for 12 weeks at 40 ° C and a relative humidity of 75%. The initial fraction of fine particles was 59.3%. The container stored for 6 weeks at 50 ° C had FPF, which was not changed compared to the original batch, i.e. at the level of 58.4%. The batch stored at 40 ° C for 8 and 12 weeks had FPF, which also was not changed from the original, i.e. at the level of 56.8% and 57.6%, respectively. The aerodynamic particle size distribution measured by NGI is shown in Figure 18. MMAD remains relatively unchanged after 6 weeks at 50 ° C, 3.94 μm, and up to 12 weeks at 40 ° C, 3.84 μm, compared to the original 3 , 54 microns. In addition, the FPF and the amount of glycopyrrolate leaving the valve stem and actuator, and from the inlet (neck) and its mouthpiece adapter, remained relatively unchanged for 3 months at elevated temperatures.

Example 11

Metered dose inhalers were prepared comprising pharmaceutical formoterol fumarate compositions as described herein. Formoterol fumarate, fumarate (±) -2-hydroxy-5 - [(1RS) -1-hydroxy-2 - [[(1RS) -2- (4-methoxyphenyl) -1-methylethyl] amino] ethyl] formanilide, also known as (±) -2'-hydroxy-5 '- [(RS) -1-hydroxy-2 - [[((RS) -p-methoxy-α-methylphenethyl] amine] ethyl] formanilide dihydrate, micronized to form particles of the active substance. The particle size distribution of micronized formoterol fumarate (FF) was determined by laser diffraction. 50% by volume of micronized particles had an optical diameter of less than 1.6 microns, and 90% by volume had an optical diameter of less than 3.9 microns.

Suspending particles were prepared as follows: 503 ml of a fluorocarbon emulsion PFOB (perfluorooctyl bromide) in phospholipid-stabilized water was prepared. 20.6 g of DSPC phospholipid (1,2-disterooyl-sn-glycero-3-phosphocholine), and 1.9 g of calcium chloride were homogenized in 403 ml of hot water (75 ° C) using a high shear mixer. During homogenization, 100 ml of PFOB was slowly added. The resulting coarse emulsion was then homogenized using a high pressure homogenizer (Model C3, Avestin, Ottawa, Calif.) At pressures up to 170 MPa for 5 treatment cycles.

The emulsion was spray dried in nitrogen using the following spray drying conditions: inlet temperature 95 ° C, outlet temperature 71 ° C, emulsion feed rate 2.4 ml / min, total gas flow 498 l / min. The size distribution of the suspending particles was determined by laser diffraction. 50% by volume of the suspending particles were less than 3 μm, the geometric standard deviation of the distribution was 1.9.

Metered dose inhalers were prepared by weighing a predetermined mass of micronized particles of the active substance and suspending particles into 15 ml coated glass vials. The target masses and the target delivered dose, assuming 20% deposition in the drive unit, are shown in Table 8 for various configurations. For each configuration, additional glass bottles were filled with the appropriate number of particles of the active substance FF without any suspending particles. The containers were sealed with 63 μl valves (Valois, Les Vaudreuil, France) and filled with 11 g (9.1 ml at 25 ° C) of HFA 134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst, UK) under overpressure through the valve stem. After injection of the propellant, the containers were sonicated for 15 seconds and shaken on a hand-type shaker for 30 minutes.

Table 8
Preset doses for cosuspension of formoterol fumarate of example 10 # configurations Particles of active substance FF, mcg / capacity Suspending Particles, mg / capacity Target delivered dose, mcg The ratio of suspending particles and particles of the active substance 6A 300 fifty 1.7 167 6B 860 4.6 58 6C 3010 16.5 16.6

A visual study of the cosuspension configurations (6A, 6B, 6C) demonstrated the absence of precipitation of crystalline FF forming particles of the active substance. The suspension slowly formed a flocculent precipitate and formed a homogeneous single exfoliated layer. For all tested concentrations, micronized active substance particles separately quickly precipitated. Images of cosuspension and conventional suspensions for comparison indicated by an asterisk are shown in Figure 19. The vials were left to settle for 24 hours without shaking. No FF crystals were visible at the bottom of any vial suspensions.

The results showed that FF crystals were associated with suspending particles. The association between the FF particles and the suspending particles was strong enough to overcome the buoyancy forces, since the FF particles did not separate from the suspending particles, and the deposition of active substance particles was successfully inhibited in each of three different composition configurations.

Example 12

Formoterol fumarate compositions were prepared for MDI in accordance with the present invention. Micronized formoterol fumarate was obtained from commercial sources and its particle size distribution, measured as described in Example 1, was characterized as d ₁₀ , d ₅₀ , d ₉₀ , constituting 0.6, 1.9 and 4.4 μm, respectively, and span 2.0. The suspending agents used were prepared in the same manner as described in Example 1. The MDI was prepared using a drug addition container (DVA), first adding half the amount of suspended particles, then filling it with microcrystalline FF, and then adding the rest half of the suspending particles to the top. Materials were added to DAV under controlled humidity conditions <10% RH. Then DAV was connected to a 4 L suspension tank. A suspension was then obtained by adding a known amount of the HFA-134a propellant (Ineos Fluor, Lyndhurst, UK) to DAV, which was then removed from the slurry tank and carefully mixed by vortexing. Then the suspension was transferred back to the tank for mixing the suspension and diluted with additional HFA-134a, obtaining the final suspension in a given concentration, thoroughly mixing with a paddle mixer. The temperature inside the vessel was maintained at 21-23 ° C throughout the entire batch preparation process. After batch recycling for 30 minutes, 14 ml aluminum tanks coated with fluorinated ethylene polymer (FEP) (Presspart, Blackburn, UK) were filled with suspension through 50 µl EPDM valves (Bespak, King's Lynn, UK). Then, the sample containers were randomly selected for a general analysis of the container to verify the correct amounts in the composition.

Then, a freshly prepared batch of cosuspension in MDI was isolated for one week, and then the initial characteristics of the product were analyzed. Aerosol performance was evaluated according to <601> (monograph United States Pharmacopeia 601). To determine the particle size distribution, the Next Generation Impactor (NGI) was used, operating at a flow rate of 30 l / min. Sample containers were placed in the drive unit with two dump actuations and two additional dump preliminary actuations. The results of five actuations were combined in NGI with an attached USP nozzle. The valve, actuator, nozzle, NGI cups, plates, and filter were rinsed using a volume distributed solvent. Sample solutions were analyzed using a chromatographic method specific for the drug. The fraction of fine particles was determined using the sum for cascades from 3 to the filter. Testing the uniformity of the delivered dose during use was performed using a dose uniformity sampling device as described in USP <601>. Samples of the two actuations were collected and analyzed at the beginning, in the middle and at the end of the application.

The figure 20 shows the uniformity of the delivered dose for FF cosuspension at a given dose of 4.8 μg per actuation. The individual delivered dose for actuation for actuation at the beginning, middle, and end was ± 25% of the average delivered dose.

Example 13

Formoterol fumarate compositions were prepared for MDI in accordance with the present invention. Micronized formoterol fumarate was obtained from commercial sources and its particle size distribution, measured as described in Example 1, was characterized as d ₁₀ , d ₅₀ , d ₉₀ , constituting 0.6, 1.9 and 4.4 μm, respectively, and span 2.0. The suspending agents used were prepared in the same manner as described in Example 1. The manufacture of MDI was carried out in the same manner as described in Example 12.

Aerosol performance was evaluated according to <601>. To determine the particle size distribution, the Next Generation Impactor (NGI) was used, operating at a flow rate of 30 l / min. Sample containers were placed in the drive unit with two dump actuations and two additional dump preliminary actuations. The results of five actuations were combined in NGI with an attached USP nozzle. The valve, actuator, nozzle, NGI cups, plates, and filter were rinsed using a volume distributed solvent. Sample solutions were analyzed using a chromatographic method specific for the drug. The fraction of fine particles was determined using the sum for cascades from 3 to the filter. The aerodynamic particle size distribution of the co-suspension composition FF was evaluated after manufacture and after storage for three months at 25 ° C and 75% RH (unprotected containers) and 40 ° C and 75% RH (protected containers wrapped in an aluminum foil bag). The aerodynamic particle size distribution shown in FIG. 21 demonstrates that the described compositions of the present invention showed the desired stability characteristics even under accelerated conditions.

Example 14

The chemical stability of formoterol fumarate (FF) included in the co-suspension composition obtained according to Example 11 was evaluated. MDI containers with FF containing HFA 134a were wrapped in an aluminum foil bag and stored at 25 ° C and 60% relative humidity and 40 ° C. and relative humidity of 75% for thirteen and six months, respectively. Similarly, MDI containers with FF containing HFA 227ea were wrapped in an aluminum foil bag and stored at 25 ° C. and 60% relative humidity and at 40 ° C. and 75% relative humidity for six months. The impurity content F, the characteristic product of FF degradation, and the total impurity content were determined by reverse phase HPLC analysis as follows: each container was cooled, opened by incision and the contents of the containers were transferred to a centrifuge tube; the contents were dissolved in an organic solvent, and then an aqueous solvent was added to precipitate the excipient (DSPC) from the solution; the solution was centrifuged to give a clear supernatant solution; and each sample solution was analyzed using a C18 column of 4.6 * 150 mm and with a particle size of 3.0 μm. The column temperature was maintained at 30 ° C. The injection volume was 20 μl and the flow rate was set to 1 ml / min and its detection was carried out by determining the UV absorption at 214 nm. The gradient was used by mixing aqueous phosphate buffer, pH 3.1, and acetonitrile, 17% acetonitrile for the first 27 minutes, then 50% acetonitrile for 30 seconds, and then 75% acetonitrile for 6.5 minutes and 17% acetonitrile in for 8 minutes. Impurities were described as a percentage of the area of the peak area for formoterol (adjusted for relative sensitivity coefficients when available). As shown in FIG. 22 (or in Tables 9 and 10), the co-suspension obtained using crystalline FF particles of the active substance suspended in HFA 134a with suspending particles was chemically stable for 18 months at a temperature of 25 ° C. and relative humidity of 60%, and, in contrast to the non-suspended composition of formoterol dried by spray drying, showed a higher degradation rate under the same storage conditions. Similarly, particles of the crystalline FF active substance formed a chemically stable cosuspension in HFA 227a, as shown in Table 11.

Table 9
Chemical stability of spray-dried suspending particles with FF in MDI with FF containing HFA 134a at 25 ° C / 60% RH, wrapped in an aluminum foil bag Time (months) 0 2 3 12 eighteen The content of impurities F (%) Nd 0.12% 0.04% 1.16% 2.77% Total impurity content (%) 0.62% 1.42% 1.75% 2.33% 4.39% ND = not defined

Table 10
Chemical stability of crystalline FF, suspended with suspending particles in MDI with FF containing HFA 134a at 25 ° C / 60% RH, wrapped in an aluminum foil bag Time (months) 0 one 2 3 6 10 13 The content of impurities F (%) 0.05% 0.08% 0.08% 0.14% 0.06% 0.22% 0.35% The total content of impurities (%) 0.44% 0.32% 0.32% 0.37% 0.18% 0.45% 0.64% at 40 ° C / 75% RH wrapped in an aluminum foil bag Time (months) 0 one 2 3 6 The content of impurities F (%) 0.05% 0.11% 0.31% 1.18% 1.74% The total content of impurities (%) 0.44% 0.41% 0.75% 1.58% 2.54%

Table 11
Chemical stability of crystalline FF, suspended with suspending particles in MDI with FF containing HFA 227a at 25 ° C / 60% RH, wrapped in an aluminum foil bag Time (months) 0 one 2 3 6 The content of impurities F (%) 0.04 0.06 0,07 0.13 0.05 Total impurity content (%) 0.4 0.3 0.3 0.4 0.1 at 40 ° C / 75% RH wrapped in an aluminum foil bag Time (months) 0 one 2 3 6 Impurity Content F 0.04 0.08 0.18 0.80 1.14 Total impurities 0.40 0.39 0.53 1.13 1,56

Example 15

The micronized formoterol fumarate dihydrate (FF) (Inke, SA, Barcelona, Spain) used in this example had the following particle size distribution determined by laser diffraction: 50% by volume of micronized particles had an optical diameter of less than 1.9 μm, 90% by the volume had an optical diameter of less than 4.1 microns. Four batches of suspending particles were prepared by spray drying as described in Example 1. All four batches were spray dried from an aqueous solution; concentration in solution and spray drying parameters are shown in table 12.

Table 12
Suspension Particle Configurations Used in Example 15 # Powder composition C _f in mg / ml Spray Drying Options Particle size distribution Feed rate in ml / min T _{at the entrance} to ° C T _{at the exit} in ° C Total gas flow in standard l / min VMD in microns GSD HA 100% trehalose 80 10 150 82 385 1,62 2.20 XB 100% HP-β-cyclodextrin 80 10 one hundred 68 885 1,61 2.21 XC 100% Ficoll PM 70 80 10 one hundred 70 885 1.19 2.27 Xd 100% Inulin 80 10 one hundred 70 885 1.23 2.20

Electron micrographs of the suspending particles showed different morphologies and are shown in Figures 23 to 26, where Figure 23 shows a micrograph of the suspending particles of trehalose, Figure 24 shows a micrograph of the suspending particles of HP-β-cyclodextrin, and Figure 25 shows a micrograph of the suspending particles of Ficoll MP 70 , and FIG. 26 is a micrograph of suspending inulin particles. Particles look spherical with a smooth surface. HP-β-cyclodextrin particles exhibit extensive surface wrinkling, exhibiting a partially deformed hollow core appearance. Particles of Ficoll MP 70 and inulin show some wrinkling of the surface, but mainly are spheroidal.

Metered dose inhalers were made by weighing 0.9 mg of micronized FF active substance particles and 60 mg of suspending particles into 15 ml coated glass vials. FF was combined with each of the four types of suspending particles shown in Table 11. Tanks were sealed with 50 μl valves (Valois DF31 / 50 RCU, Les Vaudreuil, France) and filled with 10 ml of HFA 134a propellant (Ineos Fluor, Lyndhurst, UK) pressure through the valve stem. After injection of the propellant, the containers were sonicated for 30 seconds and shaken on a hand-type shaker for 30 minutes. As a control, for each configuration, additional inhalers were filled containing only suspending particles and only particles of the active substance.

Crystalline FF has a higher density than propellant 134a at room temperature, as well as all four types of suspending particles in the present example. Therefore, both FF and suspending particles settled on the bottom of the inhaler at room temperature. To test these inhalers for active-suspending particle interactions, indicating co-suspension, the inhalers were immersed in an ethanol bath at ≤ -10 ° C (resulting in an increased propellant density) and allowed to balance for a minimum of 30 minutes. At this temperature, the particles of the active substance FF are less dense than the propellant, and therefore they formed foam on top of the volume of the propellant, while all four types of particles of the suspending substance remained deposited on the bottom of the volume of the propellant.

The tested configurations and observation results are presented in Table 13. Particles of the active substance FF separately formed a foam layer on top of the propellant volume, and all particles of trehalose, HP-β-cyclodextrin, inulin and Ficoll PM70 were separately deposited on the bottom of the glass vial. Particles of the active substance FF in combination with suspending particles from trehalose formed a single layer of sediment, without flaking particles or floating particles in the propellant, indicating that the FF particles interact with the suspending particles of trehalose and a suspension is formed. In the case of FF particles in combination with suspending particles of HP-β-cyclodextrin, some turbidity was present in the propellant, similar to what was observed for a control tank with only suspending particles. In addition, some floating flakes, which could be FF particles, were observed; however, the solid mass of such flakes was small relative to the control vial, indicating that some, if not all FF particles, interacted with the particles of the suspending substance. Thus, this configuration is an example of incomplete co-suspension. FF particles in combination with suspending particles from inulin formed a single precipitate layer, indicating that a slurry was formed. Although some turbidity was present in this configuration, similar turbidity was observed in the control vial with inulin only. Particles of the active substance FF in combination with suspending particles from Ficoll PM70 formed a sediment layer at the bottom of the vial, indicating that cosuspension was formed. Although some turbidity and floating flakes were observed in this configuration, similar turbidity and occurrence of flakes were observed in the control vial only with Ficoll.

Table 13
Summary of tested configurations and observations Container id Content in 10 ml p134a The ratio of suspending particles and particles of the active substance Observation results Cosuspension 0-ff 0.9 mg FF undefined Formed foam on top undefined T 60 mg trehalose undefined Settled at the bottom undefined T-ff 60 mg trehalose, 0.9 mg FF 67 Sediment layer, without foam-forming particles Yes C 60 mg HP-β-cyclodextrin, undefined Sinking at the bottom, some turbidity undefined C-ff 60 mg HP-β-cyclodextrin, 0.9 mg FF 67 Solids mainly in the sediment layer at the bottom; some turbidity; the presence of some floating flakes partial

I 60 mg inulin undefined Subsidence at the bottom; some turbidity undefined I-ff 60 mg inulin, 0.9 mg FF 67 Sediment layer; without foam forming particles; some turbidity Yes F 60 mg Ficoll PM70 undefined Sinking at the bottom with some floating flakes undefined Ff 60 mg Ficoll PM70, 0.9 mg FF 67 Sediment layer; very few floating flakes Yes

Example 16

Antisuspension compositions were prepared comprising particles of the active substance, glycopyrrolate (GP) and formoterol fumarate (FF), and MDIs were prepared comprising these antisuspension compositions. The resulting antisuspension compositions included particles of the active substance GP, particles of the active substance FF, or a combination of particles of both the active substance GP and the active substance FF. GP and FF material was provided as micronized crystalline material with a particle size distribution shown in Table 14.

Suspending particles were prepared by spray-drying the emulsion at a concentration of feedstock of 80 mg / ml with the composition: 93.44% DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) and 6.56% anhydrous calcium chloride (equivalent to a ratio of 2 : 1 mol / mol DSPC: CaCl ₂ ). During the preparation of the emulsions, DSPC and CaCl _{2 were} dispersed using a high shear mixer at 8000-10000 rpm. in a container containing heated water (80 ± 3 ° C), and PFOB was slowly added during this process. Then the emulsion was processed for 6 cycles in a high pressure homogenizer (10000-25000 psi (69-172 MPa)). The emulsion was then dried by spray drying in a spray dryer equipped with a 0.42 "(1.1 cm) nozzle with a gas flow set at 18 SCFM nozzle. The drying gas flow rate was set at 72 SCFM with an inlet temperature of 135 ° C, a temperature of a yield of 70 ° C and an emulsion flow rate of 58 ml / min.

Co-suspensions were prepared by initially distributing the appropriate amount of particles of the active substance, which is micronized GP and FF, and suspending particles in a drug addition container (DAV) inside a humidity-controlled chamber (RH <5%). In the present example, suspending particles were added in three equal portions, alternating with the addition of GP and FF after the first and second additions, respectively. Then, DAV was sealed in a nitrogen atmosphere and connected to a suspension container containing 12 kg of HFA-134a (Ineos Fluor, Lyndhurst, UK). Then a suspension was formed by adding 0.5-1 kg of HFA-134a to DAV, which was then removed from the suspension container and carefully mixed by vortex movement. Then the suspension was transferred back to the tank for mixing the suspension and diluted with additional HFA-134a, obtaining the final suspension in a given concentration, thoroughly mixing with a paddle mixer. The suspension was then recycled by pump to the filling system for a minimum period of time before filling began. Mixing and recycling continued throughout the filling process. 50 μl EPDM valves (Bespak, King's Lynn, UK) were placed in 14-ml aluminum containers coated with fluorinated ethylene polymer (FEP) (Presspart, Blackburn, UK), and then purged with air, either using a vacuum crimping process or a process purging HFA-134a after crimping the valve. Then, after crimping, the containers were filled through the valve with the corresponding amount of suspension, corrected by means of a measuring cylinder.

Table 14
Particle size distribution of glycopyrrolate and formoterol fumarate Designation d ₁₀ (μm) d ₅₀ (μm) d ₉₀ (μm) Scope FF API 0.6 1.9 4.1 1.8 GP API 0.5 1.3 3.0 1.9

The double co-suspension MDIs described in this example were prepared to contain two different doses of GP and FF. In particular, a first batch of double slurry compositions was prepared to provide 18 μg GP for actuation and 4.8 μg FF for actuation ("low dose"), and a second batch of double slurry compositions was prepared to provide 36 μg GP for actuation action and 4.8 μg FF on actuation ("high dose"). In addition to the double cosuspension compositions, cosuspensions were prepared including single particle types of the active substance. These compositions included either particles of the active substance GP or particles of the active substance FF, and they were designated as “mono” suspensions or cosuspensions for “monotherapy”. Co-suspension monotherapy compositions were prepared as described for double-co-suspensions, except that they included only one type of active substance particles (either GP or FF). Co-suspensions for monotherapy were prepared and MDI for monotherapy was made so that they represented the following predetermined delivered doses: 18 μg GP per actuation, and 0.5, 1.0, 3.6 or 4.8 μg FF per actuation. Compositions and MDIs providing 0.5 μg FF and 1 μg FF per actuation are referred to as “ultra-low dose” compositions and are prepared in a similar manner on a 4 L scale.

The drug-specific aerodynamic size distributions provided by the MDI containing the slurry compositions prepared according to this example were determined as described in Example 1. The proportionality of the aerodynamic size distributions of the GPs obtained for low and high dose double slurries, as well as the equivalence between double slides and cuspensions for monotherapy, shown in figure 21. Similarly, the proportionality of the aerodynamic distributions of size FF obtained for double cosuspensions and cosuspensions for monotherapy, including ultralow, low and high dose compositions, are shown in FIG. 22.

The uniformity of the delivered dose from MDI for ultra low dose FF monotherapy was also measured as described in Example 1. DDU for MDI with FF containing 0.5 μg per actuation and 1.0 μg per actuation is shown in Figure 29. Achieved the desired uniformity of the delivered dose, which demonstrates the suitability of the present invention for a uniform delivery of ultra-low doses. To evaluate whether the combination of GP and FF in one composition would lead to a deterioration in the properties of aerosol particles relative to compositions comprising a single active substance, the aerosol properties of cosuspension compositions relative to suspension compositions comprising only one active substance were evaluated. As can be seen in FIG. 30, the aerosol characteristics of the combined slurry composition comprising both the active substance GP and the active substance FF did not differ from the aerosol characteristics provided by the suspension compositions comprising either GP or FF separately. Thus, no combination effects were detected.

Example 17

Micronized salmeterol xinafoate (1-hydroxy-2-naphthalene carboxylate 4-hydroxy-α1 - [[[6- (4-phenylbutoxy) hexyl] amino] methyl] -1,3-benzenedimethanol) was purchased from the manufacturer (Inke SA, Germany) and used as particles of the active substance. The particle size distribution of salmeterol xinafoate (SX) was determined by laser diffraction. 50% by volume of micronized particles had an optical diameter of less than 2 microns, 90% by volume had an optical diameter of less than 3.9 microns.

Suspending particles were prepared as follows: 150 ml of a fluorocarbon emulsion PFOB (perfluorooctyl bromide) in water stabilized with a phospholipid was prepared. 12.3 g of phospholipid DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), and 1.2 g of calcium chloride were homogenized in 100 ml of hot water (70 ° C) using a high shear mixer. During homogenization, 65 ml of PFOB was slowly added. The resulting coarse emulsion was then homogenized using a high pressure homogenizer (Model C3, Avestin, Ottawa, CA) at pressures up to 140 MPa for 3 treatment cycles.

The emulsion was dried by spray drying in nitrogen using the following spray drying conditions: inlet temperature 90 ° C, outlet temperature 69 ° C, emulsion feed rate 2.4 ml / min, total gas flow rate 498 l / min. The size distribution of the suspending particles, VMD, was determined by laser diffraction. 50% by volume of the suspending particles were less than 2.7 μm, the geometric standard deviation for the distribution was 2.0. In addition, the aerodynamic size distribution of the suspending particles was determined using a time-of-flight particle meter. 50% by volume of the suspending particles had an aerodynamic particle diameter of less than 1.6 microns. The large difference between the aerodynamic particle diameter and the optical particle diameter indicates that the suspending particles had a low particle density <0.5 kg / L.

Metered dose inhalers were prepared by weighing 2 mg of SX active substance particles and 60 mg of suspending particles into aluminum containers coated with a 19 ml fluorinated ethylene polymer (Presspart, Blackburn, UK). The ratio of the suspending particles to the particles of the active substance was 30. The target delivered dose, assuming a deposit of 20% in the drive unit, was 10 μm. The containers were sealed with 63 μl valves (Valois, Les Vaudreuil, France) and filled with 11 g (9.1 ml at 25 ° C) of 10 ml of HFA 134a (1,1,1,2-tetrafluoroethane) under overpressure through the valve stem. After injection of the propellant, the containers were sonicated for 15 seconds and shaken on a hand-type shaker for 30 minutes. The tanks were equipped with polypropylene drive devices with a 0.3 mm hole (# BK 636, Bespak, King's Lynn, UK). Additional inhalers for visual examination of the quality of the suspension were made using 15 ml glass vials, including the compared sample, filled only with micronized SX. Aerosol performance was evaluated as described in Example 1. MMAD was 3.7 μm and the fine particle fraction was 48%. Since the SX crystals that form the particles of the active substance and the propellant practically coincided in density at 15 ° C-20 ° C, visual examination was carried out on glass bottles that were heated up to 30 ° C-35 ° C in a water bath. Under these conditions, particles of the active substance SX, manufactured separately, quickly settled, but there were no visible SX crystals at the bottom of the container with a slurry suspension.

Particles of the active substance, which is a micronized salmeterol xinafoate, are co-suspended by association with suspending particles of low density, which were made as described in this document. The association between the salmeterol crystals and the suspending particles was strong enough to overcome the buoyancy forces, since it was observed that the settling of the crystals was inhibited.

Claims (140)

1. A pharmaceutical composition for treating a disease or lung disorder delivered from a metered-dose inhaler, comprising: a suspension medium comprising a pharmaceutically acceptable propellant; a plurality of particles of an active substance containing an active substance selected from an active substance that is a long acting muscarinic receptor antagonist (LAMA) and an active substance that is a long acting β ₂ adrenergic receptor agonist (LABA); and a plurality of respirable suspending particles, wherein the plurality of suspending particles are substantially insoluble in the suspension medium and include dry perforated microstructures containing a phospholipid, the total mass of the suspending particles exceeds the total mass of the particles of the active substance, and the plurality of particles of the active substance are associated with the plurality of suspending particles with the formation of cosuspension. 2. The pharmaceutical composition according to claim 1, in which the active substance included in the particles of the active substance is an active substance LAMA selected from glycopyrrolate, tiotropium, trospium and any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 3. The pharmaceutical composition according to claim 2, in which the particles of the active substance contain glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 4. The pharmaceutical composition according to claim 3, in which the particles of the active substance contain crystalline glycopyrrolate. 5. The pharmaceutical composition according to claim 3, in which the particles of the active substance glycopyrrolate are included in the suspension medium in a concentration sufficient to provide a delivered dose of glycopyrrolate to actuate the inhaler with a metered dose selected from from about 2 μg to about 200 μg per cast action, from about 10 micrograms to about 150 micrograms per actuation and from about 15 micrograms to about 80 micrograms per actuation. 6. The pharmaceutical composition of claim 3, wherein the concentration of glycopyrrolate included in the slurry is from about 0.04 mg / ml to about 2.25 mg / ml. 7. The pharmaceutical composition according to claim 3, in which at least 90% of the particles of the active substance glycopyrrolate by volume have an optical diameter of 7 μm or less. 8. The pharmaceutical composition according to claim 3, in which at least 50% of the particles of the active substance glycopyrrolate by volume have an optical diameter of 5 μm or less. 9. The pharmaceutical composition of claim 2, wherein the perforated microstructures are prepared using a spray drying process. 10. The pharmaceutical composition of claim 9, wherein the perforated microstructures comprise a spray-dried emulsion of perfluorooctyl bromide, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and calcium chloride in water. 11. The pharmaceutical composition according to claim 2, in which the suspending particles have a mass median aerodynamic diameter (MMAD) selected from from about 10 μm to about 500 nm, from about 5 μm to about 750 nm, and from about 1 μm to about 3 μm . 12. The pharmaceutical composition according to claim 2, in which the suspending particles have a volume median optical diameter selected from from about 0.2 microns to about 50 microns, from about 0.5 microns to about 15 microns, from about 1.5 microns to about 10 microns, and from about 2 microns to about 5 microns. 13. The pharmaceutical composition of claim 2, wherein the propellant comprises a propellant selected from an HFA propellant, a perfluorinated (PFC) propellant, and combinations thereof, and in which the propellant is substantially free of additional components. 14. The pharmaceutical composition of claim 2, wherein the ratio of the total weight of the suspending particles to the total particle weight of the active substance is selected from more than about 1.5, up to about 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. 15. The pharmaceutical composition according to claim 2, in which the ratio of the total mass of the suspending particles and the total mass of particles of the active substance is selected from from about 3: 1 to about 15: 1 and from about 2: 1 to 8: 1. 16. The pharmaceutical composition according to claim 1, in which the suspending particles remain associated with the particles of the active substance, even when they are subjected to buoyancy forces, amplified by centrifugation at an acceleration selected from accelerations of at least 1 g, at least 10 g, at least 50 g and at least 100 g. 17. A method of treating a disease or lung disorder in a patient, the method comprising:
the provision of a metered dose inhaler containing a pharmaceutically acceptable cosuspension, wherein the cosuspension contains:
suspension medium containing a pharmaceutically acceptable propellant;
a plurality of particles of an active substance containing an active substance selected from an active substance of a long-acting muscarinic receptor antagonist (LAMA) and an active substance of a long-acting β ₂ -adrenergic receptor agonist (LABA); and
a plurality of respirable suspending particles, wherein the plurality of suspending particles are substantially insoluble in the suspension medium and include dry perforated microstructures containing a phospholipid, the total mass of the suspending particles exceeds the total mass of the particles of the active substance, and where the plurality of particles of the active substance are associated with the plurality of suspending particles; and
administering the co-suspension to the patient by administering a metered-dose inhaler, wherein said administering the co-suspension composition comprises delivering a therapeutically effective amount of the active substance LAMA or LABA to the patient. 18. The method according to p. 17, in which the provision of a pharmaceutically acceptable cosuspension includes providing cosuspension containing many particles of the active substance containing the active substance LAMA. 19. The method according to p. 18, in which the active substance LAMA is selected from glycopyrrolate, tiotropium, trospium and any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 20. The method of claim 19, wherein the disease or disorder of the lungs is selected from at least one of asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, sinusitis, constriction of the blood vessels of the lungs, inflammation, allergies, shortness of breath, respiratory distress syndrome, pulmonary hypertension, narrowing of the vessels of the lungs, pneumonia associated with cystic fibrosis, and lung obstruction associated with cystic fibrosis. 21. The method according to p. 20, in which the provision of a pharmaceutically acceptable cosuspension includes the provision of cosuspension containing many particles of the active substance containing glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 22. The method according to p. 21, in which the provision of a pharmaceutically acceptable co-suspension includes providing co-suspension containing many particles of the active substance containing glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the concentration of glycopyrrolate included in the co-suspension is from about 0.04 mg / ml to about 2.25 mg / ml. 23. The method of claim 19, wherein administering the pharmaceutically acceptable slurry comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in forced expiratory volume in one second (FEV ₁ ) in a patient for 1 hour or less. 24. The method of claim 19, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in forced expiratory volume in one second (FEV ₁ ) in a patient within 0.5 hours or less. 25. The method of claim 19, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in an increase in FEV _{1 of} 150 ml or more within a time period selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less. 26. The method of claim 19, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in FEV ₁ in the patient within 0.5 hours or less, and providing a clinically significant increase in FEV ₁ for a period of time, 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. 27. The method of claim 20, wherein administering a pharmaceutically acceptable co-suspension comprises administering to a patient a dose of an active LAMA substance selected from 200 μg or less, 150 μg or less, 100 μg or less, 75 μg or less, 50 μg or less, and 25 mcg or less per metered dose inhaler. 28. The method according to p. 20, in which the introduction of a pharmaceutically acceptable co-suspension includes administering to the patient a dose of a glycopyrrolate or its pharmaceutically acceptable salt, ester, isomer or solvate selected from about 150 μg or less, about 80 μg or less, about 40 μg, about 20 μg or less; and about 10 μg or less per dose metered dose inhaler. 29. The method of claim 23, wherein administering a pharmaceutically acceptable co-suspension comprises administering to a patient a dose of an active LAMA substance selected from 200 μg or less, 150 μg or less, 100 μg or less, 75 μg or less, 50 μg or less, and 25 mcg or less per actuation of a metered dose inhaler. 30. The method of claim 23, wherein administering the pharmaceutically acceptable co-suspension comprises administering to the patient a dose of a glycopyrrolate or a pharmaceutically acceptable salt, ester, isomer or solvate thereof selected from about 150 μg or less, about 80 μg or less, about 40 μg or less than about 20 μg or less and about 10 μg or less per dose metered dose inhaler. 31. The method of claim 19, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in inspiratory capacity. 32. A method for respiratory delivery of an active substance of a long-acting muscarinic receptor antagonist (LAMA) or a long-acting β ₂ -adrenergic receptor agonist active substance (LABA) to a patient, the method comprising:
the provision of a metered-dose inhaler comprising a container containing a pharmaceutically acceptable cosuspension containing:
suspension medium containing a pharmaceutically acceptable propellant;
a plurality of active substance particles containing an active substance selected from an active substance LAMA and an active substance LABA; and
a plurality of respirable suspending particles, wherein the plurality of suspending particles are substantially insoluble in the suspension medium and include dry perforated microstructures containing a phospholipid, the total mass of the suspending particles exceeds the total mass of the particles of the active substance, and where the plurality of particles of the active substance are associated with the plurality of suspending particles for the formation of cosuspension; and
actuating a metered dose inhaler to provide respiratory delivery of the active substance LAMA or LABA to the patient. 33. The method according to p. 32, in which the provision of pharmaceutically acceptable cosuspension includes providing cosuspension containing many particles of the active substance containing the active substance LAMA. 34. The method according to p. 33, in which the active substance LAMA is selected from glycopyrrolate, tiotropium, trospium and any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 35. The method according to p. 34, in which the active substance LAMA is a glycopyrrolate, including its pharmaceutically acceptable salts, esters, isomers or solvates. 36. The method of claim 33, wherein administering the metered dose inhaler to provide respiratory delivery of the LAMA active substance comprises delivering the LAMA active substance to a patient with a uniform delivery dose (DDU) selected from DDU ± 30% or better, DDU ± 25 % or better, and DDU ± 20% or better, during the empty tank. 37. The method of claim 33, wherein activating the metered dose inhaler to provide respiratory delivery of the LAMA active substance comprises delivering the LAMA active substance with an initial fraction of fine particles and an initial fraction of fine particles delivered from a metered dose inhaler essentially is maintained, so that during the emptying of the container, the fraction of fine particles delivered from the metered dose inhaler is maintained within 80% of the initial fraction of fine particles. 38. The method according to p. 37, in which during the emptying of the container, the fraction of fine particles delivered from the inhaler with a measured dose is maintained within 90% of the initial fraction of fine particles. 39. The method according to claim 37, wherein during the emptying of the container, the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction. 40. The pharmaceutical composition according to claim 1, in which the active substance included in the particles of the active substance is an active substance LABA selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol and indacaterol and any pharmaceutically acceptable salts, esters, isomers thereof or solvates. 41. The pharmaceutical composition according to p. 40, in which the particles of the active substance contain formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 42. The pharmaceutical composition according to p. 41, in which the particles of the active substance contain crystalline formoterol. 43. The pharmaceutical composition according to p. 41, in which the particles of the active substance formoterol are included in the composition at a concentration sufficient to provide a delivered dose of formoterol selected from from about 1 μg to about 30 μg, from about 0.5 μg to about 10 μg, from about 2 μg to 5 μg, from about 2 μg to about 10 μg, from about 5 μg to about 10 μg, and from 3 μg to about 30 μg per dose metered dose inhaler. 44. The pharmaceutical composition according to p. 41, in which the particles of the active substance formoterol are included in the composition in a concentration sufficient to provide a delivered dose of formoterol selected from up to about 30 μg, up to about 10 μg, up to about 5 μg, up to approximately 2.5 μg, up to approximately 2 μg or up to approximately 1.5 μg per actuation of a metered dose inhaler. 45. The pharmaceutical composition according to p. 41, in which the concentration of formoterol included in the suspension is selected from from about 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. 46. The pharmaceutical composition according to p. 41, in which at least 90% of the particles of the active substance formoterol by volume have an optical diameter of 5 μm or less. 47. The pharmaceutical composition according to p. 41, in which at least 50% of the particles of the active substance formoterol by volume have an optical diameter of 2 μm or less. 48. The pharmaceutical composition of claim 40, wherein the perforated microstructures are obtained using a spray drying process. 49. The pharmaceutical composition of claim 48, wherein the perforated microstructures comprise a spray-dried emulsion of perfluorooctyl bromide, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and calcium chloride in water. 50. The pharmaceutical composition according to p. 40, in which the suspending particles have a mass median aerodynamic diameter (MMAD) selected from from about 10 microns to about 500 nm, from about 5 microns to about 750 nm, and from about 1 micron to about 3 microns . 51. The pharmaceutical composition of claim 40, wherein the suspending particles have a volume average optical diameter selected from from about 0.2 microns to about 50 microns, from about 0.5 microns to about 15 microns, from about 1.5 microns to about 10 microns and from about 2 microns to about 5 microns. 52. The pharmaceutical composition of claim 40, wherein the propellant comprises a propellant selected from an HFA propellant, a PFC propellant, and combinations thereof, and in which the propellant is substantially free of additional components. 53. The pharmaceutical composition according to p. 40, in which the ratio of the total mass of the suspending particles and the total particle mass of the active substance is selected from more than about 1.5, up to about 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. 54. The pharmaceutical composition according to p. 40, in which the ratio of the total mass of the suspending particles and the total particle mass of the active substance is selected from from about 3: 1 to about 15: 1 and from about 2: 1 to about 8: 1. 55. The pharmaceutical composition according to p. 40, in which the suspending particles remain associated with the particles of the active substance, even when they are subjected to buoyancy forces, amplified by centrifugation at an acceleration selected from accelerations of at least 1 g, at least 10 g, at least 50 g and at least 100 g. 56. The method according to p. 17, in which the provision of a pharmaceutically acceptable co-suspension includes the provision of co-suspension containing many particles of the active substance containing the active substance LABA. 57. The method according to p. 56, in which the active substance included in the particles of the active substance is an active substance LABA selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol and indacaterol and any pharmaceutically acceptable salts, esters, isomers or solvates. 58. The method of claim 57, wherein the disease or disorder of the lungs is selected from at least one of asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, sinusitis, constriction of the blood vessels of the lungs, inflammation, allergies, shortness of breath, respiratory distress syndrome, pulmonary hypertension, narrowing of the vessels of the lungs, pneumonia associated with cystic fibrosis, and lung obstruction associated with cystic fibrosis. 59. The method according to p. 57, in which the provision of a pharmaceutically acceptable co-suspension includes the provision of co-suspension containing many particles of the active substance containing formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 60. The method according to p. 59, in which the provision of a pharmaceutically acceptable co-suspension includes the provision of co-suspension containing many particles of the active substance containing formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, and the concentration of formoterol included in the co-suspension is selected from about 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. 61. The method according to p. 57, in which the introduction of the pharmaceutical composition includes the introduction of the pharmaceutical composition in an amount leading to a clinically significant increase in the increase in forced expiratory volume in one second (FEV ₁ ) in a patient within 1 hour or less. 62. The method of claim 57, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in FEV ₁ in the patient within 0.5 hours or less. 63. The method of claim 57, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in an increase in FEV _{1 of} 150 ml or more within a time period selected from 0.5 hours or less, 1 hour or less, and 1.5 hours or less. 64. The method of claim 57, wherein administering the pharmaceutically acceptable co-suspension comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in FEV ₁ in the patient within 0.5 hours or less and providing a clinically significant increase in FEV ₁ for the time period selected from up to 4 hours, up to 6 hours and up to 8 hours or more. 65. The method of claim 57, wherein administering a pharmaceutically acceptable co-suspension comprises administering to a patient a dose of an active LABA substance selected from from about 1 μg to about 50 μg, from about 1 μg to about 30 μg, from about 2 μg to about 5 μg , from about 2 μg to about 10 μg, from about 5 μg to about 10 μg, and from about 3 μg to about 30 μg per actuation. 66. The method of claim 57, wherein administering the pharmaceutically acceptable cosuspension includes administering to the patient a dose of formoterol or a pharmaceutically acceptable salt, ester, isomer or solvate thereof 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 and up to about 1.5 μg per actuation. 67. The method of claim 57, wherein administering the pharmaceutical composition comprises administering the pharmaceutical composition in an amount resulting in a clinically significant increase in lung capacity. 68. The method according to p. 32, in which the provision of a pharmaceutically acceptable cosuspension includes the introduction of cosuspension containing many particles of the active substance containing the active substance LABA. 69. The method according to p. 68, in which the active substance LABA is selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol and indacaterol and any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 70. The method according to p. 69, in which the active substance LABA is formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 71. The method of claim 69, wherein administering a metered dose inhaler to provide respiratory delivery of an active LABA substance, comprises delivering an active LABA substance to a patient with a uniform delivery dose (DDU) selected from DDU ± 30% or better, DDU ± 25 % or better and DDU ± 20% or better, during the empty tank. 72. The method of claim 69, wherein activating the metered dose inhaler to provide respiratory delivery of the LABA active substance comprises delivering the LABA active substance with an initial fraction of fine particles, and an initial fraction of fine particles delivered from a metered dose inhaler, essentially is preserved, so that during the emptying of the container, the fraction of fine particles delivered from the inhaler with a measured dose is kept within 80% of the initial fraction of fine particles. 73. The method according to p. 72, in which during the emptying of the container, the fraction of fine particles delivered from the inhaler with a metered dose is maintained within 90% of the initial fraction of fine particles. 74. The method according to p. 73, in which during the emptying of the container, the fraction of fine particles delivered from the inhaler with a metered dose is maintained within 95% of the initial fraction of fine particles. 75. A metered-dose inhaler for delivering an active substance of a long acting muscarinic receptor antagonist (LAMA) or an active substance of a β ₂ long-acting adrenergic receptor agonist (LABA), the metered-dose inhaler includes:
a container containing a pharmaceutically acceptable cosuspension containing:
suspension medium containing a pharmaceutically acceptable propellant;
a plurality of active substance particles containing an active substance selected from an active substance LAMA and an active substance LABA; and
a plurality of respirable suspending particles, wherein the plurality of suspending particles are substantially insoluble in the suspension medium and include dry perforated microstructures containing a phospholipid, the total mass of the suspending particles exceeds the total mass of the particles of the active substance, and the plurality of particles of the active substance are associated with the plurality of suspending particles to form cosuspension;
where the active substance LAMA or LABA, included in a pharmaceutically acceptable slurry, is chemically stable for a period of at least 18 months when stored at 5 ° C. 76. The metered-dose inhaler of claim 75, wherein the active substance LAMA or LABA included in a pharmaceutically acceptable suspension is chemically stable for a period of at least 18 months when stored at 25 ° C. 77. The metered dose inhaler according to claim 75, wherein the LAMA or LABA active substance included in the pharmaceutically acceptable suspension is a LABA active substance selected from bambuterol, clenbuterol, formoterol, salmeterol, carmoterol and indacaterol and any pharmaceutically acceptable salts thereof. esters, isomers or solvates. 78. A metered-dose inhaler according to claim 77, wherein the active substance LABA is formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof. 79. The metered-dose inhaler according to claim 78, wherein the level of formation of N- (2-hydroxy-5- (1- (2-hydroxy-5- (1-hydroxy-2- (1- (4-methoxyphenyl) propane) -2-ylamino) ethyl) phenylamino) -2- (1- (4-methoxyphenyl) propan-2-ylamino) ethyl) phenyl) acetamide in pharmaceutically acceptable cosuspension does not exceed approximately 0.15% after exposure to a temperature of 40 ° C and relative humidity of 75% for one month. 80. The metered dose inhaler according to claim 78, wherein the level of formation of N- (2-hydroxy-5- (1- (2-hydroxy-5- (1-hydroxy-2- (1- (4-methoxyphenyl) propane) -2-ylamino) ethyl) phenylamino) -2- (1- (4-methoxyphenyl) propan-2-ylamino) ethyl) phenyl) acetamide does not exceed approximately 0.5% in a pharmaceutically acceptable suspension after exposure to a temperature of 40 ° C and relative humidity of 75% for one month. 81. A pharmaceutical composition for treating a disease or disorder of a lung delivered from a metered dose inhaler, comprising:
suspension medium containing a pharmaceutically acceptable hydrofluoroalkane (HFA) propellant;
a plurality of particles of the active substance containing glycopyrrolate, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, the particles of the active substance being included in the suspension medium at a concentration sufficient to provide a delivered dose of glycopyrrolate from about 15 μg to about 80 μg per cast the action of a metered dose inhaler; and
a plurality of respirable suspending particles, wherein the plurality of suspending particles are substantially insoluble in the suspension medium and include dry perforated microstructures containing a phospholipid and having a median volumetric optical diameter of from about 1.5 μm to about 10 μm, the total mass of the suspending particles exceeds the total mass particles of the active substance, and a plurality of particles of the active substance are associated with a plurality of suspending particles to form a suspension. 82. The pharmaceutical composition according to p. 81, in which the ratio of the total mass of the suspending particles and the total particle mass of the active substance is selected from from about 3: 1 to about 15: 1 and from about 2: 1 to about 8: 1. 83. A pharmaceutical composition for treating a disease or disorder of a lung delivered from a metered dose inhaler, comprising:
suspension medium containing a pharmaceutically acceptable hydrofluoroalkane (HFA) propellant;
a plurality of particles of the active substance containing formoterol, including any pharmaceutically acceptable salts, esters, isomers or solvates thereof, the particles of the active substance being included in the suspension medium in a concentration sufficient to provide a delivered dose of formoterol from about 2 μg to about 10 μg per cast the action of a metered dose inhaler; and
a plurality of respirable suspending particles, wherein the plurality of suspending particles are substantially insoluble in the suspension medium and include dry perforated microstructures containing a phospholipid and having a median volumetric optical diameter of from about 1.5 μm to about 10 μm, the total mass of the suspending particles exceeds the total mass particles of an active substance, and a plurality of particles of an active substance are associated with a plurality of suspending particles, and said plurality of particles of an active substance and associated with a plurality of suspending particles to form kosuspenzii. 84. The pharmaceutical composition according to p. 83, in which the ratio of the total mass of the suspending particles and the total particle mass of the active substance is selected from from about 3: 1 to about 15: 1 and from about 2: 1 to about 8: 1. 85. A method for respiratory delivery of an active substance of a long acting muscarinic receptor antagonist (LAMA) to a patient, the method comprising:
the provision of a metered-dose inhaler comprising a container containing a pharmaceutically acceptable cosuspension containing:
suspension medium containing a pharmaceutically acceptable hydrofluoroalkane (HFA) propellant;
many particles of the active substance containing glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and
a plurality of respirable suspending particles, wherein the plurality of suspending particles are substantially insoluble in the suspension medium and include dry perforated microstructures containing a phospholipid, the total mass of the suspending particles exceeds the total mass of the particles of the active substance, and the plurality of particles of the active substance are associated with the plurality of suspending particles to form suspensions; and
actuating a metered dose inhaler to ensure glycopyrrolate is delivered to the patient with DDU (metered dose uniformity) ± 20% or better during emptying of the reservoir. 86. The method of claim 85, wherein administering the metered dose inhaler to provide respiratory delivery of the glycopyrrolate to the patient comprises delivering the glycopyrrolate with the initial fraction of fine particles, and the initial fraction of fine particles delivered from the metered dose inhaler is substantially maintained, so that during the emptying of the container, the fraction of fine particles delivered from the inhaler with a metered dose remains within 80% of the initial fraction of fine particles. 87. The method according to p. 86, in which during the emptying of the container, the fraction of fine particles delivered from the metered dose inhaler is maintained within 90% of the initial fraction of fine particles. 88. The method according to p. 87, in which during the emptying of the container, the fraction of fine particles delivered from the inhaler with a metered dose is maintained within 95% of the initial fraction of fine particles. 89. A method for respiratory delivery of an active substance of a long acting muscarinic receptor antagonist (LABA) to a patient, the method comprising:
the provision of a metered-dose inhaler comprising a container containing a pharmaceutically acceptable cosuspension containing:
suspension medium containing a pharmaceutically acceptable hydrofluoroalkane (HFA) propellant;
a plurality of particles of the active substance containing formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and
a plurality of respirable suspending particles, wherein the plurality of suspending particles are substantially insoluble in the suspension medium and include dry perforated microstructures containing a phospholipid, the total mass of the suspending particles exceeds the total mass of the particles of the active substance, and where the plurality of particles of the active substance are associated with the plurality of suspending particles with the formation of a suspension; and
actuating a metered-dose inhaler to provide respiratory delivery of glycopyrrolate to a patient with a uniform delivery dose (DDU) of ± 20% or better during the course of emptying the container. 90. The method according to p. 89, in which the actuation of the metered dose inhaler to provide respiratory delivery of formoterol to the patient includes the delivery of formoterol with the initial fraction of fine particles, and the initial fraction of fine particles delivered from the metered dose inhaler is essentially preserved, so that during the emptying of the container, the fraction of fine particles delivered from the inhaler with a metered dose remains within 80% of the initial fraction of fine particles. 91. The method according to p. 90, in which during the emptying of the container, the fraction of fine particles delivered from the metered dose inhaler is maintained within 90% of the initial fraction of fine particles. 92. The method according to claim 91, wherein during the emptying of the container, the fine particle fraction delivered from the metered dose inhaler is maintained within 95% of the initial fine particle fraction. 93. A method of treating a disease or lung disorder in a patient, comprising:
the provision of a metered dose inhaler containing a pharmaceutically acceptable cosuspension, wherein the cosuspension contains:
suspension medium containing a pharmaceutically acceptable hydrofluoroalkane (HFA) propellant;
many particles of the active substance containing glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and
a plurality of respirable suspending particles, wherein the plurality of suspending particles are substantially insoluble in the suspension medium and include dry perforated microstructures containing a phospholipid, the total mass of the suspending particles exceeds the total mass of the particles of the active substance, and where the plurality of particles of the active substance are associated with the plurality of suspending particles with the formation of cosuspension; and
administering a co-suspension to a patient by administering a metered-dose inhaler, wherein said administering a co-suspension composition includes delivering a dose of 150 μg or less of glycopyrrolate to actuate a metered-dose inhaler and leading to a clinically significant increase in forced expiratory volume in one second (FEV ₁ ) in the patient. 94. The method of claim 93, wherein the lung disease or disorder is selected from at least one of asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, sinusitis, constriction of the blood vessels of the lungs, inflammation, allergies, shortness of breath, respiratory distress syndrome, pulmonary hypertension, narrowing of the vessels of the lungs, pneumonia associated with cystic fibrosis, and lung obstruction associated with cystic fibrosis. 95. A method of treating a disease or lung disorder in a patient, the method comprising:
the provision of a metered dose inhaler containing a pharmaceutically acceptable cosuspension, wherein the cosuspension contains:
suspension medium containing a pharmaceutically acceptable hydroxyfluoroalkane (HFA) propellant;
a plurality of particles of the active substance containing formoterol, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and
a plurality of respirable suspending particles, wherein the plurality of suspending particles are substantially insoluble in the suspension medium and include dry perforated microstructures containing a phospholipid, the total mass of the suspending particles exceeds the total mass of the particles of the active substance, and where the plurality of particles of the active substance are associated with the plurality of suspending particles with the formation of cosuspension; and
administering a co-suspension to a patient by administering a metered-dose inhaler, wherein said administering a co-suspension composition includes delivering a dose of 10 μg or less formoterol to actuate a metered-dose inhaler and leading to a clinically significant increase in forced expiratory volume in one second (FEV ₁ ) in the patient. 96. The method of claim 95, wherein the disease or lung disorder is selected from at least one of asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, sinusitis, constriction of the blood vessels of the lungs, inflammation, allergies, shortness of breath, respiratory distress syndrome, pulmonary hypertension, narrowing of the vessels of the lungs, pneumonia associated with cystic fibrosis, and lung obstruction associated with cystic fibrosis. 97. The method of claim 93, wherein said administering a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 150 mcg. 98. The method of claim 93, wherein said administering a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 100 μg. 99. The method of claim 93, wherein said administering a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 80 mcg. 100. The method of claim 93, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 150 μg, and said administration leads to an increase in FEV ₁ of at least 150 ml within 0.5 hours or less. 101. The method of claim 93, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 100 μg, and said administration leads to an increase in FEV ₁ of at least 150 ml within 0.5 hours or less. 102. The method of claim 93, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 80 μg, and said administration leads to an increase in FEV ₁ of at least 150 ml within 0.5 hours or less. 103. The method of claim 93, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 150 μg, and said administration leads to an increase in FEV ₁ of at least 200 ml within 1.0 hour or less. 104. The method of claim 93, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 100 μg, and said administration leads to an increase in FEV ₁ of at least 200 ml within 1.0 hour or less. 105. The method of claim 93, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 80 μg, and said administration leads to an increase in FEV ₁ of at least 200 ml within 1.0 hour or less. 106. A method of treating a disease or lung disorder in a patient, the method comprising:
the provision of a metered dose inhaler containing a pharmaceutically acceptable cosuspension, wherein the cosuspension contains:
suspension medium containing a pharmaceutically acceptable hydrofluoroalkane (HFA) propellant;
many particles of the active substance containing glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and
a plurality of respirable suspending particles, wherein the plurality of suspending particles are substantially insoluble in the suspension medium and include dry perforated microstructures containing a phospholipid, the total mass of the suspending particles exceeds the total mass of the particles of the active substance, and where the plurality of particles of the active substance are associated with the plurality of suspending particles with the formation of cosuspension; and
administering a co-suspension to a patient by administering a metered-dose inhaler, wherein said administering a co-suspension composition includes delivering a dose of 150 μg or less of glycopyrrolate to actuate a metered-dose inhaler and leading to a clinically significant increase in patient FEV ₁ within 0.5 hours or less, and a clinically significant increase in forced expiratory volume in one second (FEV ₁ ) persists up to 12 hours. 107. The method of claim 106, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 150 μg. 108. The method of claim 106, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 100 μg. 109. The method according to p. 106, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 80 mcg. 110. The method of claim 106, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 150 μg, and said administration leads to an increase in FEV ₁ of at least 150 ml within 0.5 hours or less, and clinically a significant increase in FEV ₁ persists for at least 12 hours. 111. The method of claim. 106, wherein said administering comprises administering a composition kosuspenzionnoy delivered dose glikopirrolyata no more than 100 micrograms, and said administering results in an increase in FEV ₁ of at least 150 ml within 0.5 hours or less, and clinically a significant increase in FEV ₁ persists for at least 10 hours. 112. The method of claim 106, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 80 μg, and said administration leads to an increase in FEV ₁ of at least 150 ml within 0.5 hours or less, and clinically a significant increase in FEV ₁ persists for at least 8 hours. 113. The method of claim 106, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 150 μg, and said administration leads to an increase in FEV ₁ of at least 200 ml within 1.0 hour or less, and clinically a significant increase in FEV ₁ persists for at least 12 hours. 114. The method of claim 106, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 100 μg, and said administration leads to an increase in FEV ₁ of at least 200 ml within 1.0 hour or less, and clinically a significant increase in FEV ₁ persists for at least 10 hours. 115. The method of claim 106, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 80 μg, and said administration leads to an increase in FEV ₁ of at least 200 ml within 1.0 hour or less, and clinically a significant increase in FEV ₁ persists for at least 8 hours. 116. A method of treating a disease or lung disorder in a patient, the method comprising:
the provision of a metered dose inhaler containing a pharmaceutically acceptable cosuspension, wherein the cosuspension contains:
suspension medium containing a pharmaceutically acceptable hydrofluoroalkane (HFA) propellant;
many particles of the active substance containing glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and
a plurality of respirable suspending particles, wherein the plurality of suspending particles are substantially insoluble in the suspension medium and include dry perforated microstructures containing a phospholipid, the total mass of the suspending particles exceeds the total mass of the particles of the active substance, and where the plurality of particles of the active substance are associated with the plurality of suspending particles with the formation of cosuspension; and
administering a co-suspension to a patient by administering a metered-dose inhaler, wherein said administering a co-suspension composition includes delivering a dose of 150 μg or less of glycopyrrolate to actuate a metered-dose inhaler, and in at least 50% of the patients, FEV ₁ increases from the initial level, selected from (i) increase in forced expiratory volume in one second (FEV ₁₎ from baseline of at least 200 ml, and (ii) an increase of 12% or FEV ₁ from baseline combined with an overall increase for FEV ₁ less th least 150 ml. 117. The method according to p. 116, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 150 mcg. 118. The method of claim 116, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 100 μg. 119. The method of claim 116, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 80 μg. 120. The method of claim 116, wherein, for at least 60% of the patient population, said administration of a co-suspension composition results in an increase in FEV ₁ from a baseline selected either (i) from an increase in FEV ₁ from a baseline of at least 200 ml, or (ii) from an increase of 12% or FEV ₁ from the baseline in combination with a total increase of FEV ₁ of at least 150 ml. 121. The method of claim 116, wherein, for at least 80% of the patient population, said administration of a co-suspension composition results in an increase in FEV ₁ from a baseline selected either (i) from an increase in FEV ₁ from a baseline of at least 200 ml, or (ii) from an increase of 12% or FEV ₁ from the baseline in combination with a total increase of FEV ₁ of at least 150 ml. 122. A method for treating a disease or disorder of a lung in a patient, the method comprising:
the provision of a metered dose inhaler containing a pharmaceutically acceptable cosuspension, wherein the cosuspension contains:
a suspension medium containing a pharmaceutically acceptable hydrofluoroalkane (HFA) propellant;
many particles of the active substance containing glycopyrrolate, including pharmaceutically acceptable salts, esters, isomers or solvates thereof; and
a plurality of respirable suspending particles, wherein the plurality of suspending particles are substantially insoluble in the suspension medium and include dry perforated microstructures containing a phospholipid, the total mass of the suspending particles exceeds the total mass of the particles of the active substance, and where the plurality of particles of the active substance are associated with the plurality of suspending particles with the formation of cosuspension; and
administering a co-suspension to a patient by administering a metered-dose inhaler, wherein said administering a co-suspension composition includes delivering a dose of 150 μg or less of glycopyrrolate to actuate a metered-dose inhaler and results in a clinically significant increase in inspiratory capacity (IC) in the patient. 123. The method according to p. 122, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 150 μg. 124. The method of claim 123, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 100 μg. 125. The method of claim 123, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 80 μg. 126. The method of claim 123, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 150 μg, and said administration leads to an increase in inspiratory capacity (IC) of at least 300 ml within a time period selected from 1 hours or less and 2 hours or less. 127. The method of claim 123, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 150 μg, and said administration leads to an increase in IC of at least 150 ml within a time period selected from 1 hour or less and 2 hours or less. 128. The method of claim 122, wherein said administration of a co-suspension composition comprises administering a delivered dose of glycopyrrolate of not more than 150 μg, and said administration leads to an increase in inspiratory capacity (IC) of at least 100 ml within a time period selected from 1 hours or less and 2 hours or less. 129. The pharmaceutical composition according to any one of paragraphs. 1-16, in which the particles of the active substance include a pharmaceutically acceptable salt of glycopyrrolate selected from salts of fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl acetate or triphenyl acetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate and benzenesulfonate. 130. The pharmaceutical composition of claim 129, wherein the pharmaceutically acceptable salt of the glycopyrrolate is selected from salts of fluoride, chloride, bromide and iodide. 131. The pharmaceutical composition of claim 130, wherein the pharmaceutically acceptable salt of the glycopyrrolate is 3 - [(cyclopentylhydroxyphenylacetyl) oxy] -1,1-dimethylpyrrolidinium bromide. 132. The pharmaceutical composition according to any one of paragraphs. 1 and 40-55, in which the particles of the active substance include a pharmaceutically acceptable salt, ester or isomer of formoterol. 133. The pharmaceutical composition according to p. 132, in which the pharmaceutically acceptable salt, ester or isomer of formoterol is a salt of formoterol selected from salts of hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, maleic, acetic, dairy, citric, tartaric, ascorbic, amber , glutaric, gluconic, tricarballic, oleic, benzoic, p-methoxybenzoic, salicylic, o- and p-hydroxybenzoic, p-chlorobenzoic, methanesulfonic, p-toluenesulfonic and 3-hydroxy-2-naphthalenecarboxylic acids. 134. The pharmaceutical composition according to claim 133, wherein the pharmaceutically acceptable salt, ester or isomer of formoterol is formoterol fumarate. 135. A metered-dose inhaler according to any one of paragraphs. 75 or 76, in which the pharmaceutical composition comprises particles of an active substance, including a pharmaceutically acceptable salt of glycopyrrolate selected from salts of fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl acetate or triphenyl acetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methanesulfonate and benzene. 136. A metered dose inhaler according to claim 135, wherein the pharmaceutically acceptable glycopyrrolate salt is selected from the salts of fluoride, chloride, bromide and iodide. 137. The metered-dose inhaler according to claim 136, wherein the pharmaceutically acceptable glycopyrrolate salt is 3 - [(cyclopentylhydroxyphenylacetyl) oxy] -1,1-dimethylpyrrolidinium bromide. 138. Inhaler with a metered dose according to any one of paragraphs. 78-80, wherein the pharmaceutically acceptable salt, ester or isomer of formoterol is a formoterol salt selected from hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, maleic, acetic, milk, lemon, tartaric, ascorbic, amber, glutaric salts tricarballyloic, oleic, benzoic, p-methoxybenzoic, salicylic, o- and p-hydroxybenzoic, p-chlorobenzoic, methanesulfonic, p-toluenesulfonic and 3-hydroxy-2-naphthalene carboxylic acids. 139. A metered dose inhaler according to claim 138, wherein the pharmaceutically acceptable salt, ester or formoterol isomer is formoterol fumarate. 140. The pharmaceutical composition according to any one of paragraphs. 1-2, 6-16, 40-41, 43-55, 81-84 and 129-134, in which the particles of the active substance include respirable particles of crystalline active substance.

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