TR2023007361T2 - A PROCESS FOR THE PREPARATION OF DRY POWDER COMPOSITIONS FOR INHALATION - Google Patents

Abstract

The invention relates to a process for the preparation of dry powder pharmaceutical compositions and compositions obtained by said process which are used in the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases.

Description

Description A METHOD FOR PREPARATION OF DRY POWDER INHALATION COMPOSITIONS Technical Field The invention relates to a method for preparing dry powder pharmaceutical compositions for the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases. State of the Art Obstructive pulmonary disease is a significant public health problem. Asthma, chronic obstructive pulmonary disease (COPD) and other obstructive airway diseases are chronic diseases that are highly prevalent in the general population. These obstructive airway diseases are manifested by chronic inflammation affecting the entire respiratory tract. The obstruction is usually intermittent and reversible in asthma, but progressive and irreversible in COPD. The drugs combine pharmacological activity with pharmaceutical properties. Their desired performance characteristics include physical and chemical stability, ease of processing, accurate and reproducible delivery to the target organ, and availability at the site of action. For dry powder inhalers (DPIs), these objectives can be met with a suitable powder formulation, an efficient measurement system, and a carefully selected device. Dry powder inhalers are well-established devices for delivering pharmaceutically active substances to the airways to treat respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Pharmaceutical compositions for inhalation used in the treatment of obstructive airway diseases can contain a variety of active ingredients, such as long-acting muscarinic antagonists (LAMAs), long-acting beta-agonists (LABAs), short-acting beta-2 agonists (SABAs), corticosteroids, and nonselective dopamine agonists. It is crucial that active substances, such as long-acting muscorinic antagonists (LAMAs), which can be highly effective even at low doses, be delivered to the lungs in efficient and sufficient quantities to achieve the desired effect. Because it is difficult to deliver sufficient amounts of these active substances, including those from the LAMA group and particularly tiotropium, glycopyrronium, ipratropium, aclidinium, oxitropium, or daratropium, to the lungs, the amounts required for treatment per dose are very small. Therefore, these active substances must be diluted with pharmaceutically acceptable carriers. Inhalers are well-established devices for the inhalation of pharmaceutically active substances into the respiratory system. Such active agents commonly administered by inhalation include bronchodilators such as β2 agonists and anticholinergics, corticosteroids, anti-allergics, and other agents that can be effectively administered by inhalation, thus increasing the therapeutic index of the active agent and reducing side effects. Most DPI formulations consist of micronized medication blended with larger carrier particles, which increase flow, reduce aggregation, and aid dispersion. A combination of intrinsic physicochemical properties, particle size, shape, surface area, and morphology influences interaction forces and aerodynamic properties, which in turn determine liquefaction, distribution, lung delivery, and deposition in the peripheral airways. Small drug particles are likely to agglomerate. Such agglomeration can be prevented by using appropriate carriers or carrier admixtures. It also helps control the fluidity of the drug leaving the delivery device and ensures the accuracy and consistency of the active ingredients reaching the lungs. Changes in powder particle size are known to significantly affect lung deposition and, consequently, efficacy. Drug particles and carrier particles are entrained in this airflow, but only fine drug particles enter the deep recesses of the lungs (the site of action of the drug). Inert excipients deposit either in the mouth or in the upper lungs. Similarly, cohesive forces between drug and carrier particles play a significant role in this distribution process. If cohesion is too strong, interrupting the airflow may not be sufficient to separate the drug from the carrier particles, resulting in low deposition efficiency. On the other hand, if cohesion is undesirably weak, significant amounts of drug particles may naturally adhere within the mouth or upper lungs, resulting in reduced deposition efficiency. Therefore, particle size differences between the carrier and drug are important for optimizing cohesive forces and ensuring content uniformity. The modern era of CTI drug delivery to the lungs began in the 1940s with the approval of the first commercial CTI product under the trade name Abbott Aerohaler®. This product was used to deliver penicillin and norethistomerone and incorporated many of the features recognizable today, including a small capsule reservoir (also known as a 'sieve') containing a lactose-based formulation designed for use in a device that distributes therapeutic particles into the airstream by utilizing the patient's inhaled airflow. The inhaler is intended to deliver a sufficient amount of medication to the patient for inhalation. The uniformity of release depends primarily on the agglomeration tendency of the dry powder within the capsule or blister, which in turn depends on both the formulation's ingredients (selected carriers and their hygroscopic properties, etc.) and the particle size distribution of these ingredients (the ratio of fine to coarse particles). Fine particle dose (FPD) is defined as the dose of aerosolized drug particles with an aerodynamic diameter of <5 microns, and fine particle fraction (FPF) is the ratio of FPD to total recovered dose. FPF is a key factor directly affecting the amount of drug reaching the patient's lungs. Drug particles smaller than µm have the greatest probability of deposition in the lungs, while those smaller than 2 µm tend to condense in the alveoli. The dose emitted from an inhaled product consists largely of particles in the 2-5 µm range, which ensures a fairly uniform distribution throughout the lungs. The selection of the carrier and, optionally, other excipients is one of the main approaches to adjusting the FPF. However, the preparation of the dry powder composition is as important as the selection of the carrier to maintain the FPF within the desired range. The process can involve several steps, such as mixing/blending, sieving, and filling the powder mixture into capsules or blisters. Mixing is the step in which different bulk material particles are brought into close contact to produce a homogeneous powder mixture. A mixture can be described as homogeneous if each sample of the mixture has the same composition and properties as the other samples. Particle segregation and agglomeration present a challenge in developing a reproducible mixing process. For dry particle mixing, the cohesive and adhesive forces acting between particles depend on molecular forces. Therefore, mixing parameters such as mixing speed and mixing volume (mixer fill volume) are as important as carrier selection to achieve both homogeneity and uniformity of composition. Patent application USRE38912E relates to a method for preparing a powder formulation for inhalation for use in a dry powder inhaler. This document emphasizes that this problem can be solved by a process in which the substance with a finer particle size distribution is added to the substance with a coarser particle size distribution through a layered mixing process. It is also stated that the sieved components are then mixed in a gravity mixer (mixing at 900 rpm), and the final mixture is passed through a granulation sieve twice more before mixing (mixing at 900 rpm). Various methods exist in the literature for incorporating active pharmaceutical ingredients (APIs) or small amounts of excipients into solid product formulations. For example, for solid formulations, methods include sequential mixing of the active ingredient and excipients in the process, forming and mixing layers of the active ingredient and excipients, and sifting the active ingredients and mixing them onto the excipient mixture. However, this document does not mention any motivation for mixing active ingredients and excipients/carriers with different properties at different mixing speeds in the method. The mixing speed of the process is not addressed in formulations containing high amounts of fine particles to ensure homogeneity of the mixture. Furthermore, instead of using multiple addition steps to ensure homogeneity of the mixture, the mixing speed of the added ingredients in the process can be adjusted. As can be seen, the prior art has not sufficiently addressed this problem. Therefore, there is still a need for innovative processes that will address the homogeneity problem and provide a standardized method for the rapid production of stable inhalation compositions with improved FPF. Objectives and Brief Description of the Invention The primary objective of the present invention is to provide a production method for the preparation of dry powder inhalation compositions that eliminates all the problems mentioned above and provides additional advantages over the relevant prior art. Another object of the present invention is to provide a new method for preparing dry powder inhalation compositions with increased uniformity and homogeneity, increased fine particle dose (FPD), and fine particle fraction (FPF). Another object of the present invention is to provide a method for preparing dry powder compositions for inhalation with improved uniformity and homogeneity. Another object of the present invention is to provide a new method for preparing dry powder compositions for inhalation that reduces the mixing time required to achieve a homogeneous composition and the resulting risk of agglomeration. Another object of the present invention is to provide a new method for preparing dry powder compositions for inhalation that eliminates the need for sieving, saves time, and consequently enables production in a single mixing vessel. Another object of the present invention is to provide a novel method for preparing dry powder compositions for inhalation, wherein the active substance(s) and the carrier are added together or separately in multiple portions. Another object of the present invention is to provide a novel method for preparing dry powder compositions for inhalation that reduces contamination in the powder mixture depending on the process duration and steps. Another object of the present invention is to provide dry powder inhalation compositions, provided by the method described above, containing at least one active substance selected from the group consisting of long-acting beta2-adrenergic agonists (LABAs), short-acting beta2 agonists (SABAs), ultra-long-acting beta2-adrenergic agonists, long-acting muscarinic antagonists (LAMAs), corticosteroids and non-selective dopamine agonists. Another object of the present invention is to provide dry powder inhalation compositions containing long-acting muscarinic antagonists (LAMAs). Another object of the present invention is to provide inhalation compositions containing tiotropium or a pharmaceutically acceptable salt thereof. Another object of the present invention is to provide inhalation compositions having appropriate particle sizes and appropriate proportions of carriers and active ingredients that ensure content uniformity and dosage accuracy in each blister or capsule. Another object of the present invention is to provide inhalation compositions having appropriate particle sizes and appropriate proportions of carriers and active ingredients that ensure effective doses of the active ingredients reach the alveoli. Another object of the present invention is to provide inhalation compositions that can be administered in blister packs or capsules using an inhaler. Another object of the present invention is to provide a blister package filled with the above-mentioned dry powder inhalation compositions. Another object of the present invention is to provide a capsule filled with the above-mentioned dry powder inhalation compositions. Another object of the present invention is to provide an inhaler that can be administered with the above-mentioned blister package or the above-mentioned capsule. Detailed Description of the Invention In accordance with the objectives summarized above, detailed features of the present invention are given herein. The invention relates to a method in which low amounts of active substance/carrier are homogenized in the formulation by different rotation speeds. The active substance should be mixed with carriers using powder mixing technology to prepare the dry powder formulation. For high dose reproducibility, it is also necessary to perform an efficient mixing process used to prepare the dry powder formulation with high content homogeneity. Therefore, the method used to prepare the dry powder formulation plays a crucial role in producing a homogeneous dry powder formulation, achieving high content uniformity and high dose reproducibility. A key aspect of the invention is the portioning of the active ingredients and carriers in the process. According to one embodiment, the total amount of active ingredients is divided into two portions to be added at different steps of the method, and the total amount of the first carrier is divided into three portions to be added at different steps of the method. Another important aspect of the invention is that the addition of the fine carrier particles is carried out at a lower mixing speed than the addition of the active ingredient. For active ingredients or carriers with a mass greater than the amount of active ingredient to be included in the formulation, prolonged mixing may be required to achieve homogeneous distribution. This can lead to undesirable situations such as the active substance bound to the carriers becoming agglomerated or smeared on the production equipment within the mixture. If an effective mixture cannot be obtained, the required quality profile of the product cannot be achieved because the formulation mixture is not homogeneous. Therefore, it is important to portion the active substance and carriers, add them in different steps of the method, and use different rotation speeds in these steps. The method according to the present invention is used to prepare a dry powder formulation containing the active substance and pharmaceutically acceptable carriers. It is a method for the preparation of dry powder inhalation compositions comprising the following steps: i. the total amount of the first carrier is divided into three portions and the first portion of the first carrier is placed in a mixing container and mixed for at least 3 minutes so that it coats the inside of the mixing container wall, ii. The total amount of active substance is divided into two portions and the first portion of active substances is placed in a mixing bowl and mixed for at least 5 minutes. iii. The second portion of the active substance and the second portion of the first carrier are placed in a mixing bowl and mixed for at least 5 minutes. iv. The third portion of the first carrier and the second carrier are placed in a mixing bowl and mixed for at least 10 minutes. It is characterized in that the rotation speed in step (ii) is 75-1000 rpm and the ratio of the rotation speed in step (ii) to the rotation speed in step (iv) is between 1.1-5.0. According to the preferred embodiment, the rotation speed in step (ii) of the method is 75-1000 rpm, preferably 75-1000 rpm. According to the preferred embodiment, the ratio of the rotation speed in step (ii) of the method to the rotation speed in step (iv) of the method is one of the most important aspects of the invention. Surprisingly, the inventors found that when the first portion of the active ingredient was mixed with coarse particulate lactose in a high shear mixer at a rotation speed of 200-600 rpm, the composition at the end of the method was more homogeneous and stable. According to a preferred embodiment, the rate of turnover in step (ii) is compared to that in step (iv). According to a preferred embodiment, the active substance is selected from the group comprising short-acting ß2 agonists (SABAs), long-acting ß2 agonists (LABAs), ultra-long-acting ß2 agonists, long-acting muscarinic antagonists (LAMAs), corticosteroids and non-selective dopamine agonists. According to a preferred embodiment, said short-acting ß2 agonists (SABAs) are selected from the group comprising: bitolterol, fenoterol, isoprenaline, levosalbutamol, orciprenaline, pirbuterol, procaterol, ritodrine, salbutamol, terbutaline, albuterol or a pharmaceutically acceptable salt or ester or an enantiomerically pure form thereof or a racemic mixture thereof or a combination of two or more. According to preferred embodiment, said long-acting ß2 agonists (LABAs) are selected from the group comprising: arformoterol, bambuterol, clenbuterol, formoterol, salmeterol or a pharmaceutically acceptable salt or ester or an enantiomerically pure form thereof or a racemic mixture or a combination of two or more. According to preferred embodiment, said ultra-long-acting ß2 agonists are selected from the group comprising: abediterol, carmoterol, indacaterol, olodaterol, vilanterol or a pharmaceutically acceptable salt or ester or an enantiomerically pure form thereof or a racemic mixture or a combination of two or more. According to preferred embodiment, said long-acting muscarinic antagonists (LAMAs) are selected from the group comprising: acyldinium, glycopyrronium, tiotropium, umeclidinium or a pharmaceutically acceptable salt or ester thereof or an enantiomerically pure form thereof or a racemic mixture thereof or a combination of two or more. According to preferred embodiment, the corticosteroid is selected from the group comprising ciclesonide, budesonide, fluticasone, aldosterone, beclomethasone, betamethasone, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluchlorolone, flumethasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, flurocortolone, flurometholone, flurandrenolone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, mometasone, parametrazone, prednisolone, prednisone, tixocortol, triamcinolone or mixtures thereof. According to a preferred embodiment, said non-selective dopamine agonist is apomorphine, a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof. According to a preferred embodiment, said long-acting muscarinic antagonists (LAMAs) is tiotropium. According to this preferred embodiment, said tiotropium salt is tiotropium bromide. To prepare a dry powder formulation for inhalation, the active substance must be diluted with suitable carriers. Carrier particles are used to improve the flowability of the active substance, thereby improving dosing accuracy, minimizing dose variability compared to the active substance alone, and facilitating their handling during manufacturing operations. Furthermore, the use of carrier particles allows the active ingredient particles to be more easily released from the medication compartments (capsule, blister, etc.), thus ensuring complete evacuation of the medication compartments with inspiratory air during inhalation, and increasing inhalation efficiency in terms of delivered dose and fine particle fraction (FPF). Depending on the preferred embodiment, said carriers comprise fine carrier particles and coarse carrier particles. Said first carriers are coarse carrier particles, and said second carriers are fine carrier particles. Said carrier is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol, and maltitol. Most preferably, said carriers are fine particle lactose and coarse particle lactose. According to a preferred embodiment, the first carrier is lactose with a coarse particle size. According to a preferred embodiment, the second carrier is lactose with a fine particle size. According to a preferred embodiment, a coarse carrier particle, such as lactose monohydrate, is applied to eliminate aggregation of drug particles and optimize lung deposition. The particle size distribution of the carrier plays a crucial role in characterizing the composition of the invention. Lactose includes lactose with a coarse particle size and lactose with a fine particle size. According to a preferred embodiment, lactose with a coarse particle size, i.e., lactose with a fine particle size, i.e., average particle size. According to one embodiment, carrier selection is essential for proper device operation and delivery of the correct amount of active ingredient to the patient. Therefore, it is essential to use lactose as a carrier in two different particle sizes (fine and coarse). The particle size distribution of the carrier plays a very important role in characterizing the composition of the invention. As used herein, 'particle size distribution' means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (Malvern analysis). Laser diffraction measures particle size distributions by measuring the angular change in intensity of scattered light as a laser beam passes through a dispersed particle sample. Large particles scatter light at small angles relative to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for creating the scattering. Particle size is reported as the volume equivalent sphere diameter. According to this measurement method, the D50 value is the dimension in microns that divides the distribution into half above and half below this diameter. In a preferred embodiment of the invention, the lactose monohydrate is present in two parts of the composition. One of these parts is fine One part is lactose monohydrate with a coarse particle size, which means that the other part is lactose monohydrate with a coarse particle size, which means that the coarse carrier particles are used to prevent agglomeration of active ingredient particles with an average particle size of less than 10 µm. Since the active ingredient and carrier particles must be separated from each other during inhalation, the shape and surface roughness of the carrier particles are particularly important. Particles with a smooth surface will separate from the active ingredients much more easily than particles of the same size but with high porosity. Since the surface energy is not evenly distributed on the coarse carrier particles, the active ingredient particles will tend to concentrate in regions with higher energy. This can prevent the separation of the active ingredient particles from the coarse carrier after pulmonary administration, especially in low-dose formulations. In this sense, the active ingredients reach the lungs more easily and Fine carrier particles are used to ensure high doses. Since the high-energy regions of the coarse carrier particles will be covered by fine carrier particles, the active substance particles will adhere to the low-energy regions; therefore, the amount of active substance particles separated from the coarse carrier particles will potentially increase. This preferred choice of carrier and particle size distribution eliminates agglomeration of the active substance particles and ensures improved stability, moisture resistance, fluidity, content uniformity and dosage accuracy. The results of the experiments conducted by the inventors are as follows: number TIOTROPIUM (%) TIOTROPIUM (%) so 3.72 It was observed that when stirred at 0.82 speed, the adhesion to the wall decreased. In process number 205502905, when the second carrier fine particle lactose was used When applied at a stirring speed of 450 rpm, a 5% loss of active ingredient due to wall adhesion was observed. According to these results, no adhesion or loss was observed when the active ingredient was mixed at 450 rpm and the second carrier at 200 rpm. The ratio of the rotation speed in step (ii) to the rotation speed in step (iv) of 1.1-5.0 provides surprisingly high uniformity and homogeneity. Accordingly, the homogeneity and stability of the final product remain constant throughout its shelf life. Furthermore, the fine particle fraction and particle size distribution of the final powder mixture are improved, ensuring accurate and consistent delivery of the active ingredients to the lungs. According to one embodiment, the pharmaceutical compositions of the invention are prepared in the following steps: i. The total amount of coarse-particle lactose is divided into three portions. and the first portion of lactose with coarse particles is placed in a mixing bowl and mixed for at least 3 minutes so that it coats the inside of the mixing bowl wall. ii. the total amount of the active substance is divided into two portions and the first portion of the active substances is placed in a mixing bowl and mixed for at least 5 minutes. iii. the second portion of tiotropium and the second portion of lactose with coarse particles are placed in a mixing bowl and mixed for at least 5 minutes. iv. the third portion of lactose with coarse particles and lactose with fine particles are placed in a mixing bowl and mixed for at least 10 minutes. characterized in that the rotation speed in step (ii) is 75-1000 rpm and the ratio of the rotation speed in step (ii) to the rotation speed in step (iv) is between 1.1-5.0. The invention also According to a preferred embodiment, the dry powder composition comprises a combination of selective long-acting muscarinic antagonists (LAMAs) or pharmaceutically acceptable salts thereof. According to a preferred embodiment, the dry powder composition comprises tiotropium bromide. According to one embodiment, the amount of tiotropium is 0.05-1.0% by weight of the total composition, preferably. According to one embodiment, the total amount of lactose is 99.00-99.95% by weight of the total composition. According to a preferred embodiment, the total amount of lactose with a fine particle size added to the mixing vessel in steps (iv) is 1-30% by weight of the total composition, preferably 5-30%, more preferably 10-30%. According to a preferred embodiment, the method for the dry powder composition of the invention comprises: - 0.05-1.0% by weight. tiotropium bromide - 99.00-99.95% by weight lactose monohydrate According to all these embodiments, the formulations given below can be used as a method for preparing the dry powder inhalation compositions of the invention. These examples do not limit the scope of the present invention and should be evaluated above. Example 1: Dry powder composition for inhalation in light of the detailed description ingredients Amount (%) Tiotropium Bromide 0.10-0.50 TOTAL 100.0 Example 2: Dry powder composition for inhalation ingredients Amount (%) Tiotropium Bromide 0.4 Fine Lactose 22.9 Coarse Lactose 76.7 TOTAL 100.0 Example 3: Dry powder composition for inhalation ingredients Amount (%) Tiotropium Bromide 0.4 TOTAL 100.0 According to a preferred embodiment, the dry powder composition of the invention is used in the treatment of respiratory diseases selected from asthma, chronic obstructive pulmonary disease, and other obstructive respiratory diseases. According to one embodiment of the invention, the dry powder composition is administered by said inhaler once a day. According to another embodiment of the invention, the dry powder composition is administered by said inhaler twice a day.

Claims (15)

REQUESTS It is a method comprising the following steps for the preparation of dry powder inhalation compositions, i. dividing the total amount of the first carrier into three portions and taking the first portion of the first carrier into a mixing container and mixing for at least 3 minutes so that it covers the inside of the mixing container wall; ii. dividing the total amount of the active substance into two portions and taking the first portion of the active substances into a mixing container and mixing for at least 5 minutes; iii. taking the second portion of the active substance and the second portion of the first carrier into a mixing container and mixing for at least 5 minutes; iv. taking the third portion of the first carrier and the second carrier into a mixing container and mixing for at least 10 minutes; The rotational speed in step (ii) is between 75-1000 rpm and the ratio of the rotational speed in step (ii) to the rotational speed in step (iv) is between 1.1-5.0. A method according to claim 1, characterized in that the active substance is selected from the group comprising short-acting ß2 agonists (SABAs), long-acting ß2 agonists (LABAs), ultra-long-acting ß2 agonists, long-acting muscarinic antagonists (LAMAs), corticosteroids and non-selective dopamine agonists. A method according to claim 2, characterized in that the said short-acting ß2 agonists (SABAs): bitolterol, fenoterol, isoprenaline, levosalbutamol, orciprenaline, pirbuterol, procaterol, ritodrine, salbutamol, terbutaline, albuterol or a pharmaceutically acceptable salt or ester thereof or an enantiomerically pure form thereof or a racemic mixture thereof or a combination of two or more. A method according to claim 2, characterized in that; said long-acting ß2 agonists (LABAs): selected from the group consisting of arformoterol, bambuterol, clenbuterol, formoterol, salmeterol or a pharmaceutically acceptable salt or ester thereof or an enantiomerically pure form thereof or a racemic mixture thereof or a combination of two or more. A method according to claim 2, characterized in that said ultra-long-acting ß2 agonists are selected from the group comprising: abediterol, carmoterol, indacaterol, olodaterol, vilanterol or a pharmaceutically acceptable salt or ester thereof or an enantiomerically pure form thereof or a racemic mixture thereof or a combination of two or more. A method according to claim 2, characterized in that said long-acting muscarinic antagonists (LAMAs) are selected from the group comprising: aslidinium, glycopyrronium, tiotropium, umeclidinium or a pharmaceutically acceptable salt or ester thereof or an enantiomerically pure form thereof or a racemic mixture thereof or a combination of two or more. A method according to claim 2, characterized in that the corticosteroid is selected from the group comprising ciclesonide, budesonide, fluticasone, aldosterone, beclomethasone, betamethasone, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluchlorolone, flumethasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, flurocortolone, flurometholone, flurandrenolone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, mometasone, parametrazone, prednisolone, prednisone, tixocortol, triamcinolone or mixtures thereof. A method according to claim 2, characterized in that said non-selective dopamine agonist is apomorphine or a pharmaceutically acceptable salt or ester thereof or an enantiomerically pure form thereof or a racemic mixture thereof. A method according to claim 6, characterized in that said long-acting muscarinic antagonists is tiotropium or a pharmaceutically acceptable salt or ester thereof or an enantiomerically pure form thereof or a racemic mixture thereof. A method according to claim 1, characterized in that said carrier is selected from the group comprising lactose, mannitol, sorbitol, inositol, xylitol, erythritol, lactitol and maltitol. A method according to any of the preceding claims, characterized in that said carrier is preferably lactose and more preferably lactose monohydrate. A method according to any of the preceding claims, characterized in that said first carrier is lactose with a coarse particle size. A method according to any of the preceding claims, characterized in that said second carrier is lactose with a fine particle size. A method according to any one of the preceding claims, characterized in that the average particle size (D50 value) of said lactose having a coarse particle size is in the range of 25-250 µm, preferably 35-100 µm. 15. 4. A method according to any of the preceding claims, characterized in that the mean particle size (D50 value) of said fine particle size lactose monohydrate is