TR2024008302T2 - A METHOD FOR PREPARATION OF DRY POWDER INHALATION COMPOSITIONS - Google Patents

Abstract

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.

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 agents, such as long-acting muscorinic antagonists (LAMAs), which can exhibit high efficacy 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 agents, including the LAMA group, and particularly tiotropium, glycopyrronium, ipratropium, aclidinium, oxitropium, or daratropium, to the lungs, the amounts per dose required for treatment are very small. Therefore, these active agents must be diluted with pharmaceutically acceptable carriers. Most DPI formulations consist of micronized drug blended with larger carrier particles that 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; This determines liquefaction, distribution, lung delivery, and peripheral airway deposition. Small drug particles are likely to agglomerate. This agglomeration can be prevented by using appropriate carriers or carrier mixtures. The carrier also helps control the fluidity of the drug exiting the device and ensures accurate and consistent delivery of active ingredients to the lungs. Changes in powder particle size are known to significantly affect lung deposition and, therefore, efficacy. Drug particles and carrier particles are entrained in this airstream, but only fine drug particles enter the deep recesses of the lungs (the site of action of the drug). The inert excipient accumulates either in the mouth or in the upper lungs. Similarly, the cohesive forces between drug and carrier particles play a significant role in this distribution process. If cohesion is too strong, interrupting airflow may not be sufficient to separate the drug from the carrier particles, resulting in low deposition efficiency. Conversely, if cohesion is undesirably weak, significant amounts of drug particles may naturally adhere within the mouth or upper lungs, resulting in low deposition efficiency. Therefore, the particle size difference between the carrier and drug is 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 process of the dry powder composition is as important as the selection of the carrier to maintain the FPF within the desired range. The method may involve several steps, such as mixing/blending, sieving, and filling the powder mixture into capsules or blisters. Various methods for incorporating active pharmaceutical ingredients (APIs) or small amounts of excipients into solid product formulations exist in the literature. For example, for solid formulations, methods exist that involve sequentially mixing the active ingredient and excipients, creating and mixing layers of active ingredient and excipients, and sifting the active ingredients and mixing them onto the excipient mixture. On the other hand, small, fine particles are often cohesive and are easily agglomerated by applying pressure. Dry granulation utilizes their cohesive properties to form larger granules without the use of binders. Fine, cohesive particles are also known. These documents do not mention any motivation for fragmenting the fine carriers and adding them in different steps and quantities to help reduce their cohesive properties. It can be seen that the prior art does not sufficiently emphasize alternative solutions to this problem. Therefore, there is still a need for innovative methods that will solve the homogeneity problem and provide a standardized method for the production of stable inhalation compositions with improved FPF. Objectives and Brief Description of the Invention The main objective of the present invention is to provide a method for the preparation of dry powder inhalation compositions that eliminates all of the aforementioned problems and provides additional advantages over the relevant prior art. The invention provides a new method for the preparation of dry powder compositions in which carriers in the formulation are portioned and added to the method at different stages. Another objective of the present invention is to provide a new method for the preparation of dry powder inhalation compositions with improved stability, 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 obtain a homogeneous composition and therefore the risk of agglomeration. Another object of the present invention is to provide a new method for preparing dry powder compositions for inhalation to which carriers are added together or separately in multiple portions. Another object of the present invention is to provide a new method for preparing dry powder compositions for inhalation that reduces contamination in the powder mixture depending on the process time and steps. 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 with appropriate particle sizes and appropriate proportions of carriers and active agents that ensure content uniformity and dosage accuracy in each blister or capsule. Another object of the present invention is to provide inhalation compositions with appropriate particle sizes and appropriate proportions of both carriers and active agents that ensure effective doses of active agents 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 pack filled with the aforementioned dry powder inhalation compositions. Another object of the present invention is to provide a capsule filled with the aforementioned dry powder inhalation compositions. Detailed Description of the Invention In accordance with the objectives outlined above, the detailed characteristics of the present invention are provided herein. To prepare the dry powder formulation, the active ingredient must be mixed with carriers using powder mixing technology. For high dose reproducibility, an effective mixing process is also necessary to prepare a dry powder formulation with high content uniformity. Therefore, the method used to prepare the dry powder formulation plays a crucial role in producing a homogeneous dry powder formulation to achieve high content uniformity and high dose reproducibility. If effective mixing is not achieved, the required product quality profile cannot be achieved because the formulation mixture is not homogeneous. Therefore, portioning and adding carriers at different steps of the method are important. The invention relates to a new method for preparing dry powder compositions in which the carriers in the formulation are divided into portions and added to the method in different steps. An important aspect of the invention is the separation of the carriers in the method into portions. The formulation of the invention contains two types of carriers, a first carrier and a second carrier. According to one embodiment, the total amount of the first carrier is divided into six fractions to be added in different steps of the method. These fractions of the first carrier are the first fraction of the first carrier, the second fraction of the first carrier, the third fraction of the first carrier, the fourth fraction of the first carrier, the fifth fraction of the first carrier, and the sixth fraction of the first carrier. According to one embodiment, the total amount of the second carrier is divided into three fractions to be added in different steps of the method. These fractions of the second carrier are the first fraction of the second carrier, the second fraction of the second carrier, the third fraction of the second carrier. According to the preferred embodiment, the present invention relates to a method for preparing dry powder inhalation compositions, comprising the following steps: i. coating the inner wall of the mixing container with the first fraction of the first carrier and mixing with a mixer ii. adding the first fraction of the second carrier and the total amount of the active ingredient to the coated mixing container and mixing with a mixer iii. adding the second fraction of the first carrier to the mixing container and mixing with a mixer iv. adding the third fraction of the first carrier to the mixing container and mixing with a mixer v. adding the fourth fraction of the first carrier to the mixing vessel and mixing with the mixer vi. sifting the mixture with a sieve vii. adding the fifth fraction of the first carrier on the sieve and mixing with the mixer viii. adding the second fraction of the second carrier to the mixing vessel and mixing with the mixer ix. adding the third fraction of the second carrier to the mixing vessel and mixing with the mixer xi. adding the sixth fraction of the first carrier on the sieve and mixing with the mixer According to an embodiment, the mixer is a low shear mixer having a rotation speed of 11-100 rpm, preferably 13-80 rpm, more preferably 15-60 rpm. According to one embodiment, the fill volume of the mixer is preferably selected between 30-80%, preferably between 32-78%, and more preferably between 44-76% of the total volume. Optimum homogeneity and fine particle dose/fraction values are achieved by the given fill volume ranges. It is not possible to obtain a homogeneous powdered drug product with a fill volume greater than 80%. Furthermore, when the fill volume exceeds 80%, it is not possible to obtain a homogeneous powdered drug product because the particles do not have sufficient space to move in the container and form agglomerates. According to one embodiment, coating the inner wall of the mixing vessel with the first fraction of the first carrier continues for at least 3 minutes in step (i). The first fraction of the first carrier is 20% by weight of the total first carrier. In one embodiment, 20% by weight of the second carrier and the total amount of active ingredient are added to the liquid mixing vessel, and mixing is continued with the mixer in step (ii) for at least 5 minutes. The most important aspect of optimizing FPD is that the active ingredient and the first portion of the second carrier are introduced at the beginning of the process. The first portion of the second carrier is 20% by weight of the total second carrier. In one embodiment, the second portion of the first carrier is added to the mixing vessel, and mixing is continued with the mixer in step (iii) for at least 5 minutes. The second portion of the first carrier is 20% by weight of the total first carrier. According to one embodiment, the addition of the third fraction of the first carrier to the mixing vessel and mixing with the mixer is continued for at least 5 minutes in step (iv). The third fraction of the first carrier is 20% by weight of the total first carrier. According to one embodiment, the addition of the fourth fraction of the first carrier to the mixing vessel and mixing with the mixer is continued for at least 5 minutes in step (v). The fourth fraction of the first carrier is 20% by weight of the total first carrier. According to one embodiment, the addition of the fifth fraction of the first carrier to the sieve to remove particles from the sieve and mixing with the mixer is continued for at least 30 minutes in step (vii). The fifth fraction of the first carrier is 10% by weight of the total first carrier. According to one embodiment, 40% by weight of the second carrier is added to the mixing vessel and mixing with the mixer is continued for at least 5 minutes in step (viii). The second fraction of the second carrier is 40% by weight of the total second carrier. According to one embodiment, in step (ix), 40% by weight of the second carrier is added to the mixing vessel and mixing with the mixer is continued for at least 5 minutes. The third fraction of the second carrier is 40% by weight of the total second carrier. According to one embodiment, the addition of the sixth fraction of the first carrier to the sieve is continued for at least 60 minutes in step (xi) to clear particles from the sieve and to mix with the mixer. The sixth fraction of the first carrier is added to the sieve by weight of the total first carrier. According to a preferred embodiment, in step (ii), the long-acting muscarinic antagonists (LAMAs) are selected from the group comprising aclidinium, 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 thereof. According to a preferred embodiment, the long-acting muscarinic antagonist (LAMA) in question is tiotropium. According to this preferred embodiment, the tiotropium salt in question is tiotropium bromide. The active substance must be diluted with suitable carriers to prepare a dry powder inhalation formulation. Carrier particles are used to improve active substance flowability, thereby improving dosage accuracy, minimizing dose variability compared to the active substance alone, and facilitating handling during manufacturing operations. In addition, the use of carrier particles allows the active substance particles to diffuse more easily from the medication compartments (capsules, blisters, etc.), thus ensuring complete evacuation of the medication compartments by the inspired air during inhalation. According to the preferred embodiment, the 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 carriers are 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 the preferred embodiment, said first carrier is coarse particle lactose. According to the preferred embodiment, said second carrier is fine particle lactose. According to the preferred embodiment, a coarse carrier particle, such as lactose monohydrate, is applied to prevent aggregation of drug particles and optimize lung deposition of the drug. The particle size distribution of the carrier plays a crucial role in the quality of the composition of the present invention. Lactose consists of lactose with a coarse particle size and lactose with a fine particle size. Lactose with a coarse particle size, i.e., an average particle size, is chosen according to the preferred application. Lactose with a fine particle size, i.e., an average particle size, is chosen according to the preferred application. The selection of a carrier for an application is crucial for ensuring 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 crucial role in the quality of the composition of the present invention. As used herein, 'particle size distribution' refers to the cumulative volume size distribution as tested by any conventionally accepted method, such as laser diffraction (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, while small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles responsible for the scattering. Particle size is reported as the volume equivalent sphere diameter. According to this measurement method, the D5O value is the dimension in microns that divides the distribution into halves above and half below this diameter. In a preferred embodiment of the invention, the lactose monohydrate composition is present in two portions. One of these fractions is lactose monohydrate, which has a fine particle size. The other fraction is lactose monohydrate, which has a coarse particle size. Coarse carrier particles are used to prevent agglomeration of active ingredient particles with an average particle size of less than 10 µm. Because 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 smooth surfaces will separate from the active ingredients much more easily than particles of the same size but with high porosity. Because surface energy is not evenly distributed on coarse carrier particles, the active ingredient particles will tend to concentrate in regions with higher energy. This can prevent the active ingredient particles from separating from the coarse carrier after pulmonary administration, especially in low-dose formulations. In this context, fine carrier particles are used to ensure that active ingredients reach the lungs more easily and in higher doses. Because the high-energy regions of the coarse carrier particles are covered by the fine carrier particles, the active ingredient particles will bind to the lower-energy regions, potentially increasing the amount of active ingredient particles separated from the coarse carrier particles. This preferred carrier selection and particle size distribution eliminates aggregation of the active ingredient particles and ensures improved stability, moisture resistance, fluidity, content uniformity, and dosage accuracy. The inventors surprisingly discovered that a small portion of the fine carrier and the remaining fine carrier after the addition of the active ingredient are added later and gradually, thus optimizing the amount of active ingredient delivered to the target organ. Small-sized fine particles are often cohesive and are easily agglomerated by applying pressure. Dry granulation utilizes their adhesive properties to form larger granules without the use of any binders. Fluidizing fine cohesive particles is considered a difficult process, but it is also known to form agglomerates. Dividing the fine carrier into portions and adding them to the method at different stages and in different amounts helps reduce the cohesive properties. This reduces the likelihood of agglomerates. The inventors have found that the present method is more advantageous for preparing mixtures containing high amounts of fine carrier, particularly in terms of achieving homogeneity and low variation in fine particle dose (FPD). In their research and development studies, the inventors found that when Tiotropium Br and fine lactose were added in the same method step, the FPD results were approximately 5.0 mcg. However, when the first fraction of Tiotropium Br and the second carrier were added in the same method step, and then portions of fine lactose were gradually added to the method, the FPD results were surprisingly found to be approximately 3.5 mcg. The method's production method was optimized by portioning the fine lactose and adding additional steps. Fine lactose, which enters the product in large quantities, is added to the method in specific stages and quantities to ensure both powder homogeneity and the dose of fine particles necessary to provide the necessary therapeutic effect in the lungs. Depending on the preferred application, the sieving process described in steps (vi) and (x) is performed. According to the preferred embodiment, the sieving mentioned in step (vi) is performed with a 125 µm sieve, and the sieving mentioned in step (x) is performed with a 125 µm sieve. In order to prevent loss of active ingredient in the invention, sieve washing is performed after steps (vi) and (x). Sieving is one of the main steps of this invention. During the sieving process, as the active ingredients, fine and coarse particles are mixed and separated, a homogeneous powder product is obtained. Sieving is not intended to reduce particle sizes. The aim is to break down any agglomerations of the active and excipients and obtain a suitable mixture. After a homogeneous powder product is obtained, product variety decreases accordingly. In addition, the fine particle dose that provides therapeutic effect in the lungs and the administered dose values are also affected by this. Finally, the stability of the product is also supported by an appropriate sieving production method. The sieve used in the method is vibration modulated and the ultrasonic frequency intensity is 25. According to one embodiment, the pharmaceutical compositions of the present invention are prepared in the following steps: i. coating the inner wall of the mixing vessel with 20% by weight coarse lactose and mixing with a mixer ii. adding 20% by weight fine lactose and the total amount of tiotropium to the coated mixing vessel and mixing with a mixer iii. adding 20% by weight coarse lactose to the mixing vessel and mixing with a mixer iv. adding 20% by weight coarse lactose and mixing with a mixer v. adding 20% by weight of coarse lactose to the mixing bowl and mixing with a mixer vi. sieving the mixture with a sieve vii. adding 10% by weight of the first carrier on the sieve and mixing with a mixer viii. adding 40% by weight of fine lactose to the mixing bowl and mixing with a mixer ix. adding 40% by weight of fine lactose to the mixing bowl and mixing with a mixer xi. adding 10% by weight of the first carrier on the sieve and mixing with a mixer The invention also provides dry powder inhalation preparations obtained by the method of the invention. According to a preferred embodiment, the dry powder composition is selective long-acting muscarinic antagonists (LAMAs) or their pharmaceutically acceptable salts in combination. According to a preferred embodiment, the dry powder composition comprises tiotropium bromide. According to one embodiment, the amount of tiotropium is 0.02-2.0% by weight of the total composition. According to one embodiment, said tiotropium has a d90 particle size of less than 15 µm, preferably less than 12 µm, more preferably less than 10 µm. According to a preferred embodiment, the total amount of lactose with a coarse particle size added to the mixing vessel in steps (iv) is 63.00% 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 2-35% by weight of the total composition, preferably 3-33%, more preferably 4-31% by weight of the total composition. According to a preferred embodiment, the method for the dry powder composition of the invention comprises: - 0.02-2.0% by weight tiotropium bromide - 2.0-35.0% by weight fine lactose monohydrate - 63.00-97.98% by weight total lactose monohydrate According to all of 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 in light of the above detailed description. Example 1: Ingredients of dry powder composition for inhalation Amount (mg) Tiotropium Bromide 0.0217 Fine Lactose 1.2140 Coarse Lactose 4.0643 TOTAL 5.3000 Example 2: Ingredients of dry powder composition for inhalation Amount (%) Tiotropium Bromide 0.41 Fine Lactose 22.91 Coarse Lactose 76.68 TOTAL 100.0 Example 3: Ingredients of dry powder composition for inhalation Amount (%) Tiotropium Bromide 0.02-2.0 fine Lactose zoo-35.00 Coarse Lactose 6300-9798 According to a preferred embodiment, the dry powder composition of the invention is used for the treatment of respiratory diseases selected from asthma and chronic obstructive pulmonary disease and other obstructive respiratory diseases. It is used in the treatment of diseases. According to one embodiment of the invention, the dry powder composition is administered once a day by said inhaler. According to another embodiment of the invention, the dry powder composition is administered twice a day by said inhaler. The dry powder composition of the invention is suitable for administration in dosage forms such as capsules, cartridges or blister packs. In the preferred embodiment, the dry powder composition is suitable for administration in a multi-dose system, more preferably in a multi-dose blister pack comprising more than one blister having air and moisture barrier properties. Each blister contains the same amount of active ingredient and carrier, which is ensured by the content uniformity of the composition and the dosage accuracy. For this invention, this is achieved by the specific selection of the carriers, their amounts and average particle sizes. In a preferred embodiment, one blister contains 3-30 mg of the dry powder composition. In the most preferred embodiment, the blister pack is configured to be loaded into a dry powder inhaler, and the composition of the invention is configured to be delivered to the lungs through the inhaler. The inhaler has means for opening the blister or capsule and ensuring the corresponding delivery of each unit dose.

Claims (1)

1.